Cannabinoid receptor ligands

ABSTRACT

There are disclosed compounds of the formula I:  
                 
 
     or a pharmaceutically acceptable salt of the compound, which exhibit anti-inflammatory and immunomodulatory activity. Also disclosed are pharmaceutical compositions containing said compounds.

[0001] This application claims priority from U.S. provisionalapplication Serial No. 60/332,911 filed Nov. 14, 2001.

BACKGROUND

[0002] The present invention relates to cannabinoid receptor ligandsand, more particularly, to compounds that bind to cannabinoid (CB₂)receptors. Compounds according to the present invention generallyexhibit anti-inflammatory and immunomodulatory activity and are usefulin treating conditions characterized by inflammation andimmunomodulatory irregularities. Examples of conditions which may betreated include, but are not limited to, rheumatoid arthritis, asthma,allergy, psoriasis, Crohn's disease, systemic lupus erythematosus,multiple sclerosis, diabetes, cancer, glaucoma, osteoporosis, renalischemia, cerebral stroke, cerebral ischemia, and nephritis. Theinvention also relates to pharmaceutical compositions containing saidcompounds.

[0003] Cannabinoid receptors belong to the superfamily of G-proteincoupled receptors. They are classified into the predominantly neuronalCB1 receptors and the predominantly peripheral CB2 receptors. While theeffects of CB1 receptors are principally associated with the centralnervous system, CB2 receptors are believed to have peripheral effectsrelated to bronchial constriction, immunomodulation and inflammation. Assuch, a selective CB2 receptor binding agent is expected to havetherapeutic utility in the control of diseases associated withinflammation, immunomodulation and bronchial constriction such asrheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis,diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebralischemia, nephritis, inflammatory disorders of the lungs andgastrointestinal tract, and respiratory tract disorders such asreversible airway obstruction, chronic asthma and bronchitis (see, e.g.,R. G. Pertwee, Curr. Med. Chem. 6(8), (1999), 635).

[0004] Various compounds have reportedly been developed which interactwith CB₂ receptors and/or which have, inter alia, anti-inflammatoryactivity associated with cannabinoid receptors. See, e.g., U.S. Pat.Nos. 5,338,753, 5,462,960, 5,532,237, 5,925,768, 5,948,777, 5,990,170,6,013,648 and 6,017,919.

SUMMARY OF THE INVENTION

[0005] In its many embodiments, the present invention provides compoundsof formula I:

[0006] or a pharmaceutically acceptable salt or solvate of saidcompound, wherein:

[0007] L¹ is a covalent bond, —CH₂—, —C(O)—, —C(O)O—, S(O₂)—, —S(O)—,—S—, —O—, —NH—, or —N(R⁷)—;

[0008] L² is —CH₂—, —C(H)(alkyl)-, —C(alkyl)₂-, —C(O)—, —SO—,—S(O_(2,))—, —C(═NR⁷)—, —C(═N—CN)— or

[0009] —C(═N—OR⁷);

[0010] L³ is a covalent bond, —C(O)— or —S(O₂)—;

[0011] R¹ is selected from the group consisting of H, halogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, —NHR⁷,—N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —S(O₂)R⁷, —Si(alkyl)_(n)(aryl)_(3-n), aryland heteroaryl, wherein each of said aryl or heteroaryl can beunsubstituted or optionally substituted with one to five moieties whichcan be the same or different and are independently selected from thegroup consisting of halogen, alkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, haloalkoxy, alkoxy, —N(R⁷)₂, —C(O)OR⁷, —C(O)N(R⁷)₂, —NC(O)R⁷,—NC(O)OR⁷, —NC(O)N(R⁷)₂, —NO₂, —CN, —S(O₂)R⁷, —S(O₂)N(R⁷)₂,—NC(═N—CN)NHR⁷, and OH, with the proviso that:

[0012] a) when R¹ is halogen, L¹ is a covalent bond;

[0013] b) when R¹ is —NHR⁷ or —N(R⁷)₂, L¹ is a covalent bond, —CH₂—,—C(O)—, —S(O₂)— or —SO—;

[0014] c) when R¹ is —C(O)R⁷ or —C(O)OR⁷, L¹ is a covalent bond, —CH₂—,—NH— or —N(alkyl)-; and

[0015] d) when R¹ is —S(O₂)R⁷ or —C(O)OR⁷, L¹ is a covalent bond, —CH₂—,—NH— or —N(alkyl)-;

[0016] R² is H, —OH, halogen, —N(R⁷)₂—, —CF₃, alkoxy, alkyl, haloalkyl,cycloalkyl or cycloalkylalkyl;

[0017] R³ and R⁴ are the same or different, and are independently H oralkyl, or R³ and

[0018] R⁴ taken together form a carbonyl group, i.e. C(═O);

[0019] R⁵ is H or alkyl;

[0020] R⁶ is selected from the group consisting of H, alkyl, haloalkyl,cycloalkyl, NHR⁷, N(R⁷)₂, aryl and heteroaryl, wherein each of said aryland heteroaryl can be unsubstituted or optionally substituted with oneto five moieties which moieties can be the same or different and areindependently selected from the group consisting of halogen, alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy and OH;

[0021] R⁷ is selected from H, alkyl, haloalkyl, cycloalkyl,heterocyclylalkyl, aryl and heteroaryl, wherein each of said aryl andheteroaryl can be unsubstituted or optionally substituted with one tofive moieties which moieties can be the same or different and areindependently selected from the group consisting of halogen, alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy and/or OH;

[0022] A is selected from phenyl, naphthyl, pyridyl, thienyl, thiazolyl,and indolyl, quinolyl, isoquinolyl, pyrazinyl, pyridazinyl, furanyl,pyrrolyl, pyrimidyl, quinazolinyl, quinoxalinyl, phthalazinyl,benzofuranyl, benzothienyl;

[0023] X is independently selected from the group consisting of H,halogen, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, alkoxycarbonyl,haloalkoxy, —N(R⁷)₂, —N(R⁷)(C(O)R⁷), —N(R⁷)(C(O)OR⁷), —NO₂ and —CN, andwhen A is selected from the group consisting of pyridyl, thienyl,thiazolyl, indolyl, quinolyl, isoquinolyl, pyrazinyl, pyridazinyl,pyrrolyl, pyrimidyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, and benzothienyl, X can be oxide;

[0024] and

[0025] n is 0-3,

[0026] with the proviso that (i) the two R⁷ moieties in —N(R⁷)₂ can bethe same or different and are independently selected, and (ii) themoiety —N(R⁵)—L³—R⁶ can optionally form a ring system.

[0027] The compounds of the present invention can be useful ascannabinoid receptor ligands. The compounds can have anti-inflammatoryactivity and/or immunomodulatory activity and can be useful in thetreatment of various medical conditions including, e.g., cutaneousT-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus,multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis,idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinaldisease, scleroderma, osteoporosis, renal ischemia, myocardialinfarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis,transplant rejection, atopic dermatitis, vasculitis, allergy, seasonalallergic rhinitis, Crohn's disease, inflammatory bowel disease,reversible airway obstruction, adult respiratory distress syndrome,asthma, chronic obstructive pulmonary disease (COPD) or bronchitis. Itis contemplated that a compound of this invention may be useful intreating one or more of the diseases listed.

DETAILED DESCRIPTION

[0028] In one embodiment, the present invention discloses cannabinoidreceptor ligands represented by structural formula I, or apharmaceutically acceptable salt or solvate thereof, wherein the variousmoieties are described above.

[0029] In a preferred embodiment of compounds of formula I, L¹ is —CH₂—,—C(O)—, —S(O)—, —C(O)O— or —S(O₂)—.

[0030] In another preferred embodiment, L² is —CH₂—, —C(H)(alkyl)-,—C(alkyl)₂-, —C(O)—, —SO— or —S(O₂)—.

[0031] In another preferred embodiment, L³ is —C(O)— or —S(O₂)—.

[0032] In another preferred embodiment, R¹ is alkyl, haloalkyl,cycloalkyl, aryl or heteroaryl, wherein each of said aryl and heteroarylcan be unsubstituted or optionally independently substituted with one tothree moieties which can be the same or different and are independentlyselected from halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy,—N(R⁷)₂, —CN, (C₁-C₆)alkoxy and OH.

[0033] In another preferred embodiment, R² is H, OH, halogen, CF₃,alkoxy, —N(R⁷)₂, alkyl, (C₁-C₆)haloalkyl, (C₃-C₅)cycloalkyl or—CH₂—(C₃-C₅)cycloalkyl.

[0034] In another preferred embodiment, R³ and R⁴ are the same ordifferent, and are independently H or C₁-C₆ alkyl.

[0035] In another preferred embodiment, R⁵ is H or C₁-C₆ alkyl.

[0036] In another preferred embodiment, R⁶ is H, C₁-C₆ alkyl, orhaloalkyl.

[0037] In another preferred embodiment, A is phenyl, naphthyl, indolyl,furanyl or pyridyl.

[0038] In another preferred embodiment, X is selected from the groupconsisting of H, halogen, alkyl, haloalkyl, (C₃-C₅)cycloalkyl, hydroxy,alkoxy, and haloalkoxy.

[0039] In another preferred embodiment, n is 0-2.

[0040] In an additional preferred embodiment, R¹ is alkyl, haloalkyl,cycloalkyl, aryl or heteroaryl, wherein each of said aryl and heteroarylcan be unsubstituted or optionally independently substituted with one tothree moieties which can be the same or different and are independentlyselected from the group consisting of halogen, alkyl, cycloalkyl,haloalkyl, haloalkoxy, (C₁-C₆)alkoxy and OH.

[0041] In an additional preferred embodiment, L¹ is —CH₂—, —C(O)O— or—S(O₂)—.

[0042] In an additional preferred embodiment, L² is —CH₂— or —S(O₂)—.

[0043] In an additional preferred embodiment, L³ is —C(O)— or —S(O₂)—.

[0044] In an additional preferred embodiment, R² is H, OH, halogen, CF₃,alkoxy, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₅)cycloalkyl or—CH₂—(C₃-C₅)cycloalkyl.

[0045] In an additional preferred embodiment, R³ and R⁴ are H.

[0046] In an additional preferred embodiment, R⁵ is H or C₁-C₆ alkyl.

[0047] In an additional preferred embodiment, R⁶ is H, C₁-C₆ alkyl, orhaloalkyl.

[0048] In an additional preferred embodiment, A is phenyl, indolyl orpyridyl.

[0049] In an additional preferred embodiment, X is selected from H,halogen, alkyl, haloalkyl, (C₃-C₅)cycloalkyl, hydroxy, alkoxy, andhaloalkoxy.

[0050] In an additional preferred embodiment, n is 0-2.

[0051] In a still additional preferred embodiment, L¹ is —C(O)O— or—S(O₂)—.

[0052] In a still additional preferred embodiment, L² is —S(O₂)—.

[0053] In a still additional preferred embodiment, L³ is —C(O)— or—S(O₂)—.

[0054] In a still additional preferred embodiment, R¹ is selected fromt-butyl, i-propyl, neopentyl, 2-trifluoromethyl-2-propyl,1,1-bis(trifluoromethyl)-1-ethyl, 2-fluorophenyl, 2,6-difluorophenyl,2-pyridyl, and 2-pyrimidyl.

[0055] In a still additional preferred embodiment, R² is H, F,(C₁-C₆)alkyl, OH, or alkoxy.

[0056] In a still additional preferred embodiment, R³ and R⁴ are H.

[0057] In a still additional preferred embodiment, R⁵ is H.

[0058] In a still additional preferred embodiment, R⁶ is CH₃ or CF₃.

[0059] In a still additional preferred embodiment, A is phenyl, indolylor pyridyl.

[0060] In a still additional preferred embodiment, X is selected from H,OH, Cl, Br, CF₃, CH₃O—, CF₃O— and CHF₂O—.

[0061] In a still additional preferred embodiment, n is 0-2.

[0062] A particularly preferred compounds of the invention arerepresented by general formulas 2 and 3:

[0063] wherein:

[0064] R¹ is selected from the group consisting of alkyl, haloalkyl,cycloalkyl, aryl and heteroaryl, wherein each of said aryl andheteroaryl can be unsubstituted or optionally substituted with one tofive moieties which moieties can be the same or different and areindependently selected from the group consisting of halogen, alkyl,cycloalkyl, haloalkyl, haloalkoxy, (C₁-C₆)alkoxy and/or OH;

[0065] R² is H, OH, F, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, alkoxy or(C₃-C₅)cycloalkyl;

[0066] R⁶ is H, C₁-C₆ alkyl or haloalkyl;

[0067] L³ is —C(O)— or —S(O₂)—; and

[0068] X is selected from H, halogen, alkyl, haloalkyl, hydroxy, alkoxy,(C₃-C₅)cycloalkyl and haloalkoxy.

[0069] In additionally preferred compounds of the formulas 2 and 3above, X is selected from —OCH₃, —OCHF₂, —OCF₃, OH or halogen and n is0-2.

[0070] In still additionally preferred compounds of formulas 2 and 3above, X is selected from —OCH₃ and chlorine.

[0071] Additional preferred compounds are represented by generalformulas 4 and

[0072] wherein, in formulas 4 and 5:

[0073] L³ is —C(O)— or —S(O₂);

[0074] R¹ is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, whereinsaid aryl and heteroaryl can be unsubstituted or optionally substitutedwith one to five moieties which can be the same or different and areindependently selected from the group consisting of halogen, OH; alkyl,cycloalkyl, haloalkyl, haloalkoxy, and/or (C₁-C₆)alkoxy

[0075] R² is H, OH, F, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, alkoxy or(C₃-C₅)cycloalkyl, CH₂—(C₃-C₅)cycloalkyl;

[0076] R⁵ is H, alkyl, or aryl

[0077] R⁶ is H, C₁-C₆ alkyl, or haloalkyl;

[0078] X is selected from the group consisting of H, halogen, alkyl,haloalkyl, (C₃-C₅)cycloalkyl, alkoxy, hydroxy and haloalkoxy; and

[0079] n is 0-2.

[0080] As used above, and throughout this disclosure, the followingterms, unless otherwise indicated, shall be understood to have thefollowing meanings:

[0081] “Patient” includes both human and animals.

[0082] “Mammal” means humans and other mammalian animals.

[0083] “Alkyl” means an aliphatic hydrocarbon group which may bestraight or branched and comprising about 1 to about 20 carbon atoms inthe chain. Preferred alkyl groups contain about 1 to about 12 carbonatoms in the chain. More preferred alkyl groups contain about 1 to about6 carbon atoms in the chain. Branched means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkylchain. “Lower alkyl” means a group having about 1 to about 6 carbonatoms in the chain which may be straight or branched. The term“substituted alkyl” means that the alkyl group may be substituted by oneor more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino,—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy and —C(O)O-alkyl.Non-limiting examples of suitable alkyl groups include methyl, ethyl,n-propyl, isopropyl and t-butyl.

[0084] “Alkynyl” means an aliphatic hydrocarbon group containing atleast one carbon-carbon triple bond and which may be straight orbranched and comprising about 2 to about 15 carbon atoms in the chain.Preferred alkynyl groups have about 2 to about 12 carbon atoms in thechain; and more preferably about 2 to about 4 carbon atoms in the chain.Branched means that one or more lower alkyl groups such as methyl, ethylor propyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term “substitutedalkynyl” means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

[0085] “Alkylene” means a difunctional group obtained by removal of ahydrogen atom from an alkyl group that is defined above. Non-limitingexamples of alkylene include methylene, ethylene and propylene.

[0086] “Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

[0087] “Heteroaryl” means an aromatic monocyclic or multicyclic ringsystem comprising about 5 to about 14 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the ring atoms is anelement other than carbon, for example nitrogen, oxygen or sulfur, aloneor in combination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyridyl-N-oxide,pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl,triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

[0088] “Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which thearyl and alkyl are as previously described. Preferred aralkyls comprisea lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

[0089] “Alkylaryl” means an alkyl-aryl- group in which the alkyl andaryl are as previously described. Preferred alkylaryls comprise a loweralkyl group. Non-limiting example of a suitable alkylaryl group istolyl. The bond to the parent moiety is through the aryl.

[0090] “Cycloalkyl” means a non-aromatic mono- or multicyclic ringsystem comprising about 3 to about 10 carbon atoms, preferably about 5to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 toabout 7 ring atoms. The cycloalkyl can be optionally substituted withone or more “ring system substituents” which may be the same ordifferent, and are as defined above. Non-limiting examples of suitablemonocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. Non-limiting examples of suitable multicycliccycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.

[0091] “Halogen” or “halo” means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine or bromine, and more preferred arefluorine and chlorine.

[0092] “Ring system substituent” means a substituent attached to anaromatic or non-aromatic ring system which, for example, replaces anavailable hydrogen on the ring system. Ring system substituents may bethe same or different, each being independently selected from the groupconsisting of aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl,alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl,aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— andY₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, and aralkyl.

[0093] “Heterocyclyl” means a non-aromatic saturated monocyclic ormulticyclic ring system comprising about 3 to about 10 ring atoms,preferably about 5 to about 10 ring atoms, in which one or more of theatoms in the ring system is an element other than carbon, for examplenitrogen, oxygen or sulfur, alone or in combination. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocyclyl can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The nitrogen or sulfur atom of the heterocyclyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, and the like.

[0094] “Heteroaralkyl” means a heteroaryl-alkyl- group in which theheteroaryl and alkyl are as previously described. Preferredheteroaralkyls contain a lower alkyl group. Non-limiting examples ofsuitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl.The bond to the parent moiety is through the alkyl.

[0095] “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is aspreviously defined. Preferred hydroxyalkyls contain lower alkyl.Non-limiting examples of suitable hydroxyalkyl groups includehydroxymethyl and 2-hydroxyethyl.

[0096] “Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, groupin which the various groups are as previously described. The bond to theparent moiety is through the carbonyl. Preferred acyls contain a loweralkyl. Non-limiting examples of suitable acyl groups include formyl,acetyl and propanoyl.

[0097] “Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

[0098] “Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

[0099] “Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

[0100] “Aralkyloxy” means an aralkyl-O— group in which the aralkyl groupis as previously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

[0101] “Alkylthio” means an alkyl-S— group in which the alkyl group isas previously described. Non-limiting examples of suitable alkylthiogroups include methylthio and ethylthio. The bond to the parent moietyis through the sulfur.

[0102] “Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

[0103] “Aralkylthio” means an aralkyl-S— group in which the aralkylgroup is as previously described. Non-limiting example of a suitablearalkylthio group is benzylthio. The bond to the parent moiety isthrough the sulfur.

[0104] “Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limitingexamples of suitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

[0105] “Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limitingexamples of suitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

[0106] “Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limitingexample of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. Thebond to the parent moiety is through the carbonyl.

[0107] “Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups arethose in which the alkyl group is lower alkyl. The bond to the parentmoiety is through the sulfonyl.

[0108] “Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parentmoiety is through the sulfonyl.

[0109] “Halogenated alkyl” or “haloalkyl” means alkyl having 1 or morehalogen atoms.

[0110] “Heteroalkyl” means straight or branched alkyl chain comprised offrom 1 to 12 carbon atoms and 1 or more heteroatoms independentlyselected from the group consisting of N, O and S.

[0111] The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

[0112] The term “optionally substituted” means optional substitutionwith the specified groups, radicals or moieties.

[0113] It should also be noted that any heteroatom with unsatisfiedvalences in the text, schemes, examples and Tables herein is assumed tohave the hydrogen atom to satisfy the valences.

[0114] When a functional group in a compound is termed “protected”, thismeans that the group is in modified form to preclude undesired sidereactions at the protected site when the compound is subjected to areaction. Suitable protecting groups will be recognized by those withordinary skill in the art as well as by reference to standard textbookssuch as, for example, T. W. Greene et al, Protective Groups in organicSynthesis (1991), Wiley, New York.

[0115] When any variable (e.g., aryl, heterocycle, R², etc.) occurs morethan one time in any constituent or in Formula III, its definition oneach occurrence is independent of its definition at every otheroccurrence.

[0116] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[0117] Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of Formula III or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)Edward B. Roche, ed., American Pharmaceutical Association and PergamonPress, both of which are incorporated herein by reference thereto.

[0118] “Solvate” means a physical association of a compound of thisinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Non-limitingexamples of suitable solvates include ethanolates, methanolates, and thelike. “Hydrate” is a solvate wherein the solvent molecule is H₂O.

[0119] “Effective amount” or “therapeutically effective amount” is meantto describe an amount of compound or a composition of the presentinvention effective in inhibiting the CDK(s) and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

[0120] The compounds of Formula III can form salts which are also withinthe scope of this invention. Reference to a compound of Formula IIIherein is understood to include reference to salts thereof, unlessotherwise indicated. The term “salt(s)”, as employed herein, denotesacidic salts formed with inorganic and/or organic acids, as well asbasic salts formed with inorganic and/or organic bases. In addition,when a compound of Formula III contains both a basic moiety, such as,but not limited to a pyridine or imidazole, and an acidic moiety, suchas, but not limited to a carboxylic acid, zwitterions (“inner salts”)may be formed and are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the Formula III may be formed, for example, byreacting a compound of Formula III with an amount of acid or base, suchas an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

[0121] Exemplary acid addition salts include acetates, ascorbates,benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

[0122] Exemplary basic salts include ammonium salts, alkali metal saltssuch as sodium, lithium, and potassium salts, alkaline earth metal saltssuch as calcium and magnesium salts, salts with organic bases (forexample, organic amines) such as dicyclohexylamines, t-butyl amines, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

[0123] All such acid salts and base salts are intended to bepharmaceutically acceptable salts within the scope of the invention andall acid and base salts are considered equivalent to the free forms ofthe corresponding compounds for purposes of the invention.

[0124] Compounds of Formula III, and salts, solvates and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

[0125] All stereoisomers (for example, geometric isomers, opticalisomers and the like) of the present compounds (including those of thesalts, solvates and prodrugs of the compounds as well as the salts andsolvates of the prodrugs), such as those which may exist due toasymmetric carbons on various substituents, including enantiomeric forms(which may exist even in the absence of asymmetric carbons), rotamericforms, atropisomers, and diastereomeric forms, are contemplated withinthe scope of this invention, as are positional isomers (such as, forexample, 4-pyridyl and 3-pyridyl). Individual stereoisomers of thecompounds of the invention may, for example, be substantially free ofother isomers, or may be admixed, for example, as racemates or with allother, or other selected, stereoisomers. The chiral centers of thepresent invention can have the S or R configuration as defined by theIUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”“prodrug” and the like, is intended to equally apply to the salt,solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers,positional isomers, racemates or prodrugs of the inventive compounds.

[0126] The compounds of the present invention can be useful ascannabinoid receptor ligands. The compounds can have anti-inflammatoryactivity and/or immunomodulatory activity and can be useful in thetreatment of various medical conditions including, e.g., cutaneousT-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus,multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis,idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinaldisease, scleroderma, osteoporosis, renal ischemia, myocardialinfarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis,transplant rejection, atopic dermatitis, vasculitis, allergy, seasonalallergic rhinitis, Crohn's disease, inflammatory bowel disease,reversible airway obstruction, adult respiratory distress syndrome,asthma, chronic obstructive pulmonary disease (COPD) or bronchitis. Itis contemplated that a compound of this invention may be useful intreating one or more of the diseases listed.

[0127] Additionally, a compound of the present invention may beco-administered or used in combination with disease-modifyingantirheumatic drugs (DMARDS) such as methotrexate, azathioprine,leflunomide, pencillinamine, gold salts, mycophenolate mofetil,cyclophosphamide and other similar drugs. They may also beco-administered with or used in combination with NSAIDS such aspiroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2selective inhibitors such as Vioxx® and Celebrex®; immunosuppressivessuch as steroids, cyclosporin, Tacrolimus, rapamycin and the like;biological response modifiers (BRMs) such as Enbrel®, Remicade®, IL-1antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules andthe like; and other anti-inflammatory agents such as p38 kinaseinhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptorantagonists, Thalidomide and other small molecule inhibitors ofpro-inflammatory cytokine production.

[0128] Also additionally, a compound of the present invention may beco-administered or used in combination with an H1 antagonist for thetreatment of seasonal allergic rhinitis and/or asthma. Suitable H1antagonists may be, for example, Claritin®, Clarinex®, Allegra®, orZyrtec®.

[0129] In another aspect, the invention provides a method for treatingrheumatoid arthritis comprising administering a compound of the formulaI in combination with compound selected from the class consisting of aCOX-2 inhibitor e.g. Celebrex® or Vioxx®; a COX-1 inhibitor e.g.Feldene®; an immunosuppressive e.g. methotrexate or cyclosporin; asteroid e.g. β-methasone; and anti-TNF-α compound, e.g. Enbrel® orRemicade®; a PDE IV inhibitor, or other classes of compounds indicatedfor the treatment of rheumatoid arthritis.

[0130] In another aspect, the invention provides a method for treatingmultiple sclerosis comprising administering a compound of the formula Iin combination with a compound selected from the group consisting ofAvonex®, Betaseron, Copaxone or other compounds indicated for thetreatment of multiple sclerosis.

[0131] In another aspect, the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I in a pharmaceutically acceptable carrier.

[0132] In yet another aspect, the invention relates to a pharmaceuticalcomposition for treating rheumatoid arthritis comprising atherapeutically effective amount of a compound of formula 1 incombination with a compound selected from the class consisting of aCOX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, ananti-TNF-α compound or other classes of compounds indicated for thetreatment of rheumatoid arthritis. In still another aspect, theinvention relates to a pharmaceutical composition for treating multiplesclerosis comprising a therapeutically effective amount of a compound offormula 1 in combination with a compound selected from the groupconsisting of Avonex®, Betaseron, Copazone or other compounds indicatedfor the treatment of multiple sclerosis.

[0133] Compounds of the present invention are generally prepared byprocesses known in the art, for example, by the processes describedbelow.

[0134] The following abbreviations are used in the procedures andschemes: aqueous (aq.), anhydrous (anhyd), n-butyl (n-Bu),n-butyllithium (n-BuLi), concentrated (conc.), diethyl ether (Et₂O),days (d), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCl), dimethylformamide (DMF), ethanol (EtOH), ethyl (Et), ethylacetate (EtOAc), hours (h), leaving group (LG), hydroxybenzotriazole(HOBT), meta-chloroperoxybenzoic acid (MCPBA), lithium diisopropylamide(LDA), methanesulfonyl chloride (MsCl), methanol (MeOH), minutes (min),methyl (Me), methyllithium (MeLi), molar (moles per liter, M),N-chlorosuccinimide (NCS), N,N-dimethylaminopyridine (DMAP), normal (N),pounds per square inch (psi), preparative thin layer chromatography(PTLC), room temperature (rt), saturated sodium chloride solution(brine), silica gel chromatography (sgc),2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON),tert-butoxycarbonyl (BOC), trifluoroacetic anhydride (TFAA),trifluoroacetic acid (TFA), trifluoromethanesulfonic anhydride (Tf₂O),and tetrahydrofuran (THF). In a typical work-up procedure, the reactionmixture is diluted with a suitable solvent, such as EtOAc, Et₂O, orCH₂Cl₂, and washed successively with appropriate acidic, basic, orneutral aqueous solutions. The organic solution is separated, dried overan appropriate drying agent such as MgSO₄ or Na₂SO₄, filtered, and thesolvent removed by evaporation.

[0135] Description of Reaction Scheme I

[0136] In step 1, a suitably protected and optionally functionalized4-(aminomethyl)piperidine derivative is dissolved in CH₂Cl₂, a tertiaryamine base added, and the resulting solution cooled to 0° C. A solutionof an arenesulfonyl chloride in CH₂Cl₂ is added. The reaction mixture isstirred at 0° C. to rt for 2-24 h, and then worked up. The product isisolated, and optionally purified by sgc.

[0137] In step 2, the product from step 1 is dissolved in a suitablesolvent, such as THF, and cooled to −78° C. n-BuLi is added, and theresulting dianion solution is stirred for 30 min, then treated with anappropriate electrophile, such as a dialkyl dicarbonate, a sulfonylfluoride, a disulfide, or elemental sulfur. The reaction is allowed toproceed at −78° C. to rt for 3-24 h, then worked up, and the product ispurified by sgc.

[0138] In step 3, the product of step 2 is dissolved in a suitablesolvent, such as MeOH or 1,4-dioxane, and an aq. base solution, such asof potassium carbonate or lithium hydroxide, is added. The reactionmixture is stirred at rt for 1-24 h and then worked up.

[0139] In step 4, the product from step 3 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and cooled to between 0° C. and −78° C. Theresulting solution is combined with a tertiary amine base and a suitableacylating or sulfonylating agent such as TFAA or Tf₂O. The reaction isallowed to proceed at a temperature between −78° C. and rt for 1-24 h.The reaction is then worked up and the crude product purified by sgc.

[0140] In step 5, the product from step 4 is dissolved in an appropriatesolvent, such as MeOH, and a suitable catalyst, such as palladiumhydroxide on carbon, is added. The reaction mixture is exposed to ahydrogen atmosphere (ambient pressure to 60 psi) for 1-24 h, and thenworked up. The product is isolated and purified by sgc or PTLC.

[0141] For the preparation of some compounds, step 2 may be omitted.

[0142] If the electrophile in step 2 is a disulfide, the product of step2 is dissolved in an appropriate solvent, such as CH₂Cl₂, treated withan oxidant such as MCPBA, and the reaction mixture stirred for 1-24 hbetween 0° C. and rt. The reaction is then worked up. The product isisolated, purified by sgc, and then used in step 3.

[0143] If the electrophile in step 2 is elemental sulfur, the product ofstep 2 is treated with a base, such as sodium hydride, in a suitablesolvent, such as THF. An appropriate electrophile is added, and thereaction mixture is stirred at 0° C. to rt for 1-24 h, then worked up,and the product isolated. This product is then dissolved in anappropriate solvent, such as CH₂Cl₂, treated with an oxidant such asMCPBA, and the reaction mixture stirred for 1-24 h between 0° C. and rt.The reaction is then worked up. The product is isolated, purified bysgc, and then used in step 3.

[0144] Optionally, step 2 may be postponed and carried out immediatelyfollowing step 4 of the synthetic sequence.

[0145] Description of Reaction Scheme II

[0146] In step 1, a solution of a dialkyl dicarbonate in an appropriatesolvent, such as CH₂Cl₂, is added to a solution of an alkylisonipecotate in the same solvent. The reaction is allowed to proceed at0° C. to rt for 2-24 h, then worked up, and the product purified by sgc.

[0147] In step 2, a solution of the product from step 1 in anappropriate solvent, such as THF, is added to a solution of a base, suchas LDA, in the same solvent and allowed to react at −78° C. to 0° C. for0.5-2 h. A suitable electrophile is added and the reaction is allowed toproceed for 2-24 h between 0° C. and rt. The reaction is worked up, andthe product is isolated and purified by sgc.

[0148] In step 3, the product from step 2 is acidified, such as with asolution of hydrogen chloride in 1,4-dioxane, and stirred at rt for 1-24h. The solvent is then removed by evaporation.

[0149] In step 4, the product from step 3 is dissolved in CH₂Cl₂ atertiary amine base added, and the resulting solution cooled to 0° C. Asolution of an appropriate arenesulfonyl chloride in CH₂Cl₂ is added.The reaction mixture is stirred at 0° C. to rt for 2-24 h, then workedup. The product is isolated and purified by sgc.

[0150] In step 5, the product from step 4 is allowed to react with amethanolic ammonia solution at rt for 2-48 h. The resulting product isisolated by evaporation of the solvent.

[0151] In step 6, a reducing agent, such as borane-methyl sulfidecomplex, is added to a suspension of the product from step 5 in anappropriate solvent, such as THF. The reaction is allowed to proceed for1-24 h between room and reflux temperatures. The reaction is quenchedwith acid, worked up, and the product isolated.

[0152] In step 7, the product from step 6 is dissolved in CH₂Cl₂ atertiary amine base added, and the resulting solution cooled to 0° C. Asolution of an arenesulfonyl chloride in CH₂Cl₂ is added. The reactionmixture is stirred at 0° C. to rt for 2-24 h, and then worked up. Theproduct is isolated, and optionally purified by sgc.

[0153] The product of step 7 can be converted to the final product viasequences presented in General Scheme I.

[0154] The product of step 7 can be accessed via an alternativefive-step route starting with an appropriately protected4-cyanopiperidine derivative. In step 1 of the alternative pathway,dissolution of the 4-cyanopiperidine derivative in a suitable solvent,such as THF, is followed by sequential treatment with a base, such asLDA, and an electrophile. The reaction mixture is stirred for 2-24 hbetween −78° C. and rt. The reaction is worked up and the product isisolated and purified by sgc.

[0155] In step 2, the product of step 1 is combined with a suitablecatalyst, for example rhodium on alumina, in methanolic ammonia solutionand exposed to hydrogen atmosphere between ambient and 60 psi pressure.The reaction mixture is filtered, worked up, and the product isolated.

[0156] In step 3, the product from step 2 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and cooled to between 0° C. and −78° C. Theresulting solution is combined with a tertiary amine base and a suitableacylating or sulfonylating agent such as TFAA or Tf₂O. The reaction isallowed to proceed at a temperature between −78° C. and rt for 1-24 h.The reaction is then worked up and the crude product purified by sgc.

[0157] In step 4, the product from step 3 is acidified, such as with asolution of hydrogen chloride in 1,4-dioxane, and stirred at rt for 1-24h. The solvent is then removed by evaporation.

[0158] In step 5, the product from step 4 is dissolved in CH₂Cl₂, atertiary amine base added, and the resulting solution cooled to 0° C. Asolution of an arenesulfonyl chloride in CH₂Cl₂ is added. The reactionmixture is stirred at 0° C. to rt for 2-24 h, and then worked up. Theproduct is isolated, and optionally purified by sgc.

[0159] The product of step 5 can be converted to the final product viasequences presented in General Scheme I.

[0160] Description of Reaction Scheme III

[0161] In step 1, benzyl chloride is allowed to react withdiethanolamine in a suitable solvent, such as EtOH, for 68 h at anappropriate temperature. Subsequent treatment with thionyl chloride, inan appropriate solvent, such as 1,2-dichloroethane, affords theprotected amino-dichloride.

[0162] In step 2, the dichloride, dissolved in an appropriate solventsuch as THF, is treated with the anion generated by treatment ofcyclopropylacetonitrile with a suitable base such as sodiumbis(trimethylsilyl)amide. The reaction is allowed to proceed at 0° C.for 3 h, then worked up, and the resulting cyanopiperidine is purifiedby sgc.

[0163] In step 3, the product of step 2 is dissolved in an appropriatesolvent, such as methanolic ammonia, and combined with a suitablecatalyst, such as Raney Nickel. The reaction mixture is pressurized withhydrogen gas (typically 20-50 psi) and agitated for an appropriatelength of time. The solution is filtered and the reaction is worked up.The resulting amine is purified by sgc.

[0164] In step 4, the product of step 3 and an appropriate tertiaryamine base are dissolved in an appropriate solvent such as CH₂Cl₂ andtreated with a suitable electrophile. The reaction is allowed to proceedbetween −78° C. and rt for 1-24 h.

[0165] In step 5, the product of step 4 is dissolved in an appropriatesolvent such as CH₂Cl₂ or dichloroethane, and combined with anappropriate chlorocarboxylate reagent. The reaction is allowed toproceed for 1-72 h at a temperature between rt and 80° C., then workedup, and the product purified by sgc.

[0166] In step 6, the product of step 5 and an appropriate tertiaryamine base are dissolved in an appropriate solvent such as CH₂Cl₂ andtreated with a suitable arenesulfonyl chloride. The reaction is allowedto proceed between 0° C. and rt for 1-24 h, and is then worked up andthe product is purified by sgc.

[0167] In step 7, the product from step 6 is dissolved in a suitablesolvent, such as THF, and cooled to −78° C. n-BuLi is added, and theresulting dianion solution is stirred for 30 min, then treated with anappropriate electrophile, such as a dialkyl dicarbonate, a sulfonylfluoride, or a disulfide. The reaction is allowed to proceed at −78° C.to rt for 3-24 h, then worked up, and the product is purified by sgc. Ifa disulfide is used as the electrophile, the product is oxidized withMCPBA in CH₂Cl₂.

[0168] Description of Reaction Scheme IV

[0169] In step 1, 1-t-butoxycarbonyl-4-methylenepiperidine is stirred ina solution of TFA and CH₂Cl₂ for 1-24 h. Removal of the solvent gavecrude 4-methylenepiperidine. This crude product is then dissolved inCH₂Cl₂ a tertiary amine base added, and the resulting solution cooled to0° C. A solution of arenesulfonyl chloride in CH₂Cl₂ is added. Thereaction mixture is stirred at 0° C. to rt for 3-24 h, worked up, andthe product purified by sgc.

[0170] In step 2, the product from step 1 is dissolved in a suitablesolvent, such as THF, and cooled to −78° C. n-BuLi is added, and theresulting dianion solution is stirred for 30 min and then treated withan appropriate electrophile. The reaction is allowed to proceed at −78°C. to rt for 3-24 h further, then worked up, and the product is purifiedby sgc.

[0171] In step 3, the product from step 2 is dissolved in CH₂Cl₂ and anoxidant such as MCPBA is added. The reaction mixture is stirred at 0° C.to rt for 1-24 h, then worked up, and the crude product purified by sgc.

[0172] In step 4, the product from step 3 is dissolved in a suitablesolvent system, such as dioxane and water, and solid sodium azide isadded. The reaction is carried out for 2-24 h at rt to refluxtemperature of the solvent. The reaction is worked up and the resultingproduct can be used without further purification.

[0173] In step 5. the product from step 4 is dissolved in an appropriatesolvent such as THF. A suitable base, such as sodium hydride, andelectrophile are added successively. The reaction mixture is stirred atrt for 1-24 h, and then worked up, and the crude product purified bysgc.

[0174] In step 6, the product from step 5 is dissolved in an appropriatesolvent system, such as THF and water, and a reductant, such astriphenylphosphine, is added. The resulting mixture is stirred at rt for2-24 h. The reaction is worked up and the product can be purified bysgc.

[0175] In step 7, the product from step 6 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and cooled to −78° C. The resulting solution iscombined with a tertiary amine base and a suitable acylating orsulfonylating agent such as TFAA or Tf₂O. The reaction is allowed toproceed at −78° C. to rt for 1-24 h, before being worked up and thecrude product purified by sgc.

[0176] Alternatively, the product from step 4 can be dissolved in anappropriate solvent system, such as THF and water, and a reductant, suchas triphenylphosphine, is added. The resulting mixture is stirred at rtfor 2-24 h. The reaction is worked up and the product can be purified bysgc. Subsequently, this purified product can be dissolved in anappropriate solvent, such as CH₂Cl₂, and cooled to −78° C. The resultingsolution is combined with a tertiary amine base and a suitable acylatingor sulfonylating agent such TFAA or Tf₂O is added. The reaction isallowed to proceed at −78° C. to rt for 1-24 h, before being worked upand the crude product purified by sgc.

[0177] Description of Reaction Scheme V

[0178] In step 1, indole is dissolved in a suitable solvent, such asTHF, and cooled to −78° C. An appropriate base, such as n-BuLi, is addedand reaction mixture is stirred for 15-30 min. A solution of anappropriate electrophile, such as 2-fluorobenzenesulfonyl chloride, inTHF is added, and the reaction is allowed to proceed at −78° C. to rtfor 2-24 h. The reaction is worked up and the product purified by sgc.

[0179] In step 2, the product from step 1 is dissolved in a suitablesolvent, such as THF, and cooled to −78° C. n-BuLi is added, and theresulting solution is stirred for 30-60 min and then treated with anappropriate electrophile such as sulfur dioxide. The reaction mixture isconcentrated to minimal volume, and hexanes is added. The resultingprecipitate is then washed and taken up in an appropriate solvent, suchas CH₂Cl₂. A chlorinating agent, such as NCS, is added and the reactionmixture is stirred at rt for 2-24 h at rt. The reaction is worked up,and the product is purified by sgc.

[0180] In step 3, the product from step 2 is dissolved in a suitablesolvent, such as CH₂Cl₂, and added to a solution of a tertiary aminebase and an appropriately protected and optionally substituted secondaryamine in the same solvent. The reaction is allowed to proceed at rt for2-24 h, then worked up, and the product purified by sgc or PTLC.

[0181] Description of Reaction Scheme Va

[0182] In step 1, indole derivative is dissolved in a suitable solvent,such as DMF, THF and cooled to 0° C. An appropriate base, such as NaH,is added and the reaction mixture is stirred for 15 min. A solution ofan appropriate electrophile, such as 2-fluorophenyl disulphide, isadded, and the reaction is allowed to proceed at r.t. for 2-24 h. Theproduct may be purified via sgc or crystallization.

[0183] In step 2, the product from step 1 is dissolved in a suitablesolvent, such as DMF, THF. An appropriate base, such as NaH, is addedand the reaction mixture is stirred for 15 min. A solution of anappropriate electrophile, such as iodomethane, is added, and thereaction is allowed to proceed at r.t. for 2-24 h. The product may bepurified via sgc or crystallization.

[0184] In step 3, the product from step 2 is dissolved in THF, cooled ina dry ice/IPA bath and treated with LDA. The resulting anion is trappedwith SO₂ gas followed by reacting with NCS. The product may be purifiedvia chromatography or crystallization.

[0185] In step 4, the product from step 3 is dissolved in a suitablesolvent, such as CH₂Cl₂, and added to a solution of a tertiary amine andan appropriately protected and optionally substituted secondary amine inthe same solvent. The reaction is allowed to proceed at rt for 2-24 h.The product may be purified via sgc or crystallization.

[0186] Description of Reaction Scheme VI

[0187] In step 1, indole-2-carboxylic acid and an appropriatelyprotected, optionally substituted piperidine derivative are dissolved ina suitable solvent, such as CH₂Cl₂. HOBT, EDCl, and a tertiary aminebase are added successively, and the reaction is allowed to proceed atrt for 2-24 h. The reaction is worked up and the product purified bysgc.

[0188] In step 2, the product from step 1 is dissolved in an alcoholicsolvent, and aq. base is added. The reaction is allowed to proceed at rtfor 2-24 h before being worked up. The product can be used withoutpurification.

[0189] In step 3, the product from step 2 is dissolved in an appropriatesolvent system, such as THF and CH₂Cl₂. BOC-ON and a catalytic amount ofDMAP are added and the reaction is allowed to proceed at rt for 2-24 h.The reaction is then worked up and the crude product purified by sgc orPTLC.

[0190] In step 4, the product from step 3 is dissolved in CH₂Cl₂. An aq.base solution, such as sodium hydroxide, and a phase transfer catalyst,such as tetrabutylammonium hydrogen sulfate, are added successively andthe resulting mixture is stirred at rt for 2-24 h. After work-up, thecrude product can be purified by sgc or PTLC.

[0191] In step 5, the product from step 4 is stirred in a solution ofTFA and CH₂Cl₂ for 1-24 h. The solvent is evaporated, and the resultingproduct can be used without further purification.

[0192] In step 6, the product from step 5 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and cooled to between 0° C. and −78° C. Theresulting solution is combined with a tertiary amine base and a suitableacylating or sulfonylating agent such as TFAA or Tf₂O. The reaction isallowed to proceed at a temperature between −78° C. and rt for 1-24 h.The reaction is then worked up and the crude product purified by sgc.

[0193] Description of Reaction Scheme VII

[0194] In step 1, an ester, such as ethyl indole-2-carboxylate, andlithium aluminum hydride are stirred at 0° C. to rt for 30 min. Thereaction is quenched with water and aq. sodium hydroxide prior towork-up. The isolated alcohol intermediate is dissolved in a suitablesolvent, such as CH₂Cl₂, and an appropriate oxidant, such as manganesedioxide is added. The reaction mixture is stirred at rt for 0.5-4 h,then worked up, and the product purified by sgc.

[0195] In step 2, the product from step 1 is dissolved in CH₂Cl₂. An aq.base solution, such as sodium hydroxide, and a phase transfer catalyst,such as tetrabutylammonium hydrogen sulfate, are added successively andthe resulting mixture is stirred at rt for 2-24 h. After subsequentwork-up, the crude product can be purified by sgc.

[0196] In step 3, the product of step 2 is combined with a suitablyprotected, optionally substituted 4-aminomethylpiperidine derivative inan appropriate solvent such as CH₂Cl₂. A Lewis acid, such as titaniumtetrachloride, and a tertiary amine base are added and the reactionmixture is stirred for 2-24 h at rt. A reducing agent, such as sodiumcyanoborohydride, is added, and the reaction is allowed to continue fora further 2 h. The reaction is worked up and the crude product ispurified by sgc or PTLC.

[0197] In step 4, the product of step 3 is dissolved in a suitablesolvent, such as 1,4-dioxane, and an aq. base solution, such as oflithium hydroxide, is added. The reaction mixture is stirred at rt for1-24 h and then worked up.

[0198] In step 5, the product from step 4 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and cooled to between 0° C. and −78° C. Theresulting solution is combined with a tertiary amine base and a suitableacylating or sulfonylating agent such as TFAA or Tf₂O. The reaction isallowed to proceed at a temperature between −78° C. and rt for 1-24 h.The reaction is then worked up and the crude product purified by sgc.

[0199] Description of Reaction Scheme VIII

[0200] In step 1, methylcerium is prepared by the combination of anhyd.cerium(III) chloride and methyllithium in an appropriate solvent, suchas THF. A solution of a protected 4-cyanopiperidine derivative is addedand the reaction is allowed to proceed at −78° C. for 2-24 h. Thereaction is quenched and worked up, and the product isolated.

[0201] In step 2, the product from step 1 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and cooled to between 0° C. and −78° C. Theresulting solution is combined with a tertiary amine base and a suitableacylating or sulfonylating agent such as TFAA or Tf₂O. The reaction isallowed to proceed at a temperature between −78° C. and rt for 1-24 h.The reaction is then worked up and the crude product purified by sgc.

[0202] In step 3, the product from step 2 is acidified, such as with asolution of hydrogen chloride in 1,4-dioxane, and stirred at rt for 1-24h. The solvent is then removed by evaporation.

[0203] The product from step 3 is converted to the final productaccording to the procedure outlined in General Scheme I.

[0204] Description of Reaction Scheme IX

[0205] In step 1, a functionalized aryl methyl ether, prepared via themethod described by General Scheme I, is dissolved in an appropriatesolvent, such as CH₂Cl₂, and a Lewis acid, such as boron tribromide, isadded. The reaction mixture is stirred for 2-24 h between −78° C. andrt, then worked up, and the product isolated.

[0206] In step 2, the product of step 1 is dissolved in a polar solvent,such as DMF, and combined with an appropriate base, such as cesiumcarbonate. Bromodifluoromethane gas is introduced, and the reaction isallowed to proceed at rt to 90° C. for 2-24 h. The reaction is quenched,and the product is isolated and purified by sgc.

[0207] Description of Reaction Scheme X

[0208] In step 1, a functionalized t-butyl benzoate derivative, preparedvia the method described by General Scheme I, is dissolved in anappropriate solvent such as CH₂Cl₂ and acidified, such as with TFA. Thereaction mixture is stirred at rt for 1-24 h, then worked up, and theproduct isolated.

[0209] In step 2, the product from step 1 is combined withpentafluorophenol and EDCl in an appropriate solvent, such as CH₂Cl₂.The reaction is stirred at rt for 2-24 h, then worked up. The product isisolated and purified by sgc.

[0210] In step 3, an alcohol is added to a suspension of a base, such assodium hydride, in an appropriate solvent, such as DMF. The product fromstep 2 is then added and the resulting mixture is stirred at rt to 60°C. for 2-24 h. The reaction is worked up, the product isolated, and thenpurified by sgc.

[0211] Description of Reaction Scheme XI

[0212] In step 1, a suitably protected and optionally functionalized4-(aminomethyl)piperidine derivative is dissolved in CH₂Cl₂ a tertiaryamine base added, and the resulting solution cooled to 0° C. A solutionof 2-nitrobenzenesulfonyl chloride in CH₂Cl₂ is added. The reactionmixture is stirred at 0° C. to rt for 2-24 h, worked up, and the productisolated.

[0213] In step 2, the product of step 1 is dissolved in a suitablesolvent, such as MeOH, and an aq. base solution, such as of lithiumhydroxide, is added. The reaction mixture is stirred at rt for 1-24 hand then worked up and the product isolated.

[0214] In step 3, the product from step 2 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and cooled to between 0° C. and −78° C. Theresulting solution is combined with a tertiary amine base and a suitableacylating or sulfonylating agent such as TFAA or Tf₂O. The reaction isallowed to proceed at a temperature between −78° C. and rt for 1-24 h.The reaction is then worked up and the crude product purified by sgc.

[0215] In step 4, the product from step 3 is dissolved in an appropriatesolvent, such as MeOH, combined with conc. hydrochloric acid and asuitable catalyst, such as 10% palladium on carbon, and shaken underhydrogen atmosphere (ambient pressure to 60 psi) for 1-24 h. Thereaction mixture is filtered and worked up prior to product isolation.

[0216] In step 5, the product from step 4 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and cooled to between 0° C. and −78° C. Theresulting solution is combined with a tertiary amine base and a suitableacylating or sulfonylating agent such as cyclopentanecarbonyl chloride.The reaction is allowed to proceed at a temperature between −78° C. andrt for 1-24 h. The reaction is then worked up and the crude productpurified by sgc.

[0217] Description of Reaction Scheme XII

[0218] In step 1, a suitably protected and optionally functionalized4-(aminomethyl)piperidine derivative is dissolved in CH₂Cl₂, a tertiaryamine base added, and the resulting solution is cooled to 0° C. Asolution of 5-bromothiophene-2-sulfonyl chloride in CH₂Cl₂ is added. Thereaction mixture is stirred at 0° C. to rt for 2-24 h, worked up, andthe product isolated.

[0219] In step 2, the product from step 1 is combined with a suitablecatalyst, such as tetrakis(triphenylphosphine)palladium(0), in asuitable solvent, such as THF. An aq. solution of base, such aspotassium carbonate, is added, followed by an appropriate boronic acid,such as phenylboronic acid. The reaction mixture is stirred for 2-24 hbetween rt and reflux temperature. The reaction is then worked up. Theproduct is isolated and purified by sgc or PTLC.

[0220] Description of Reaction Scheme XIII

[0221] In step 1, a solution of thiophene and t-butyl bromide in anappropriate solvent, such as CH₂Cl₂ is added slowly to a suspension of aLewis acid, such as aluminum trichloride, in the same solvent. Thereaction mixture is stirred for 2-24 h between −78° C. and rt, thenworked up. The product is isolated and purified by distillation.

[0222] In step 2, the product from step 1 is dissolved in an appropriatesolvent, such as CH₂Cl₂, and the solution added slowly to an ice-coldsolution of chlorosulfonic acid in the same solvent. The reaction isallowed to proceed at 0° C. for 30 min, and is then quenched and theproduct isolated.

[0223] The product from step 2 is converted to the final product via theprocedure presented in General Scheme 1.

[0224] Those skilled in the art will appreciate that similar reactionsto those described in the above schemes may be carried out on othercompounds of formula I. Starting materials for the above processes areeither commercially available, known in the art, or prepared byprocedures well known in the art. Exemplary compounds of the presentinvention are set forth below in Table I. TABLE I

Cmp R¹ R² R³ R⁴ R⁶ A = L¹ L² L³ X A

H H H CF₃

CO₂ SO₂ SO₂ Cl B

H H H CH₃

CO₂ SO₂ SO₂ OCF₃ C

H H H CF₃

CO₂ SO₂ SO₂ Cl D

H H H CF₃

CO₂ SO₂ SO₂ H E

H H H CF₃

CO₂ SO₂ SO₂ Cl F

H H H CH₃

CO₂ SO₂ SO₂ Cl G

H H H CF₃

CO₂ SO₂ SO₂ Cl H i-propyl H H H CF₃

CO₂ SO₂ SO₂ Cl I

H H H CH₃

CO₂ SO₂ SO₂ H J

H H H CH₃

SO₂ SO₂ SO₂ OCH₃ K

H H H CH₃

SO₂ SO₂ SO₂ OCH₃ L

H H H CH₃

SO₂ SO₂ SO₂ OCF₂H M

H H H CH₃

SO₂ SO₂ SO₂ OCF₃ N

H H H C₂H₅

SO₂ SO₂ SO₂ OCF₂H O

H H H CH₃

SO₂ SO₂ SO₂ Cl P

H H H C₂H₅

SO₂ SO₂ SO₂ OCF₃ Q

H H H CF₃

SO₂ SO₂ SO₂ CF₃ R

H H H CF₃

SO₂ SO₂ SO₂ Cl S

H H H CF₃

SO₂ SO₂ C═O OCH₃ T

H H H CH₃

SO₂ SO₂ SO₂ H U

H H H CF₃

SO₂ SO₂ C═O OCH₃ V Br H H H CH₃

CB SO₂ SO₂ H W

H H H CH₃

CB SO₂ SO₂ H X C₃H₇ H H H CH₃

SO₂ SO₂ SO₂ OCH₃ Y

H H H CF₃

SO SO₂ C═O Cl Z

H H H CF₃

SO₂ CH₂ C═O Cl AA

H H H CF₃

S CH₂ C═O Cl AB

H H H CH₃

CH₂ SO₂ SO₂ Cl AC

H H H CH₃

CH₂ SO₂ SO₂ Cl AD

H H H CH₃

C═O SO₂ SO₂ Cl AE H H H H CF₃

CB SO₂ SO₂ H AF H H H H CH₃

CB SO₂ SO₂ H AG

H H H CH₃

SO₂ SO₂ SO₂ H AH Si(CH₃)₃ H H H CH₃

CB SO₂ SO₂ Cl AI Br H H H CH₃

CB SO₂ SO₂ H AJ

H H H CH₃

NH SO₂ SO₂ H AK

OCH₃ H H CH₃

CO₂ SO₂ SO₂ Cl AL

CH₃ H H CF₃

SO₂ SO₂ SO₂ Cl AM

CH₃ H H CH₃

SO₂ SO₂ SO₂ Cl AN

CH₃ H H CF₃

CO₂ SO₂ SO₂ Cl AO

H H H CF₃

SO₂ SO₂ SO₂ H AP

H H H CF₃

CO₂ SO₂ SO₂ OCH₃ AQ

F H H CF₃

SO₂ SO₂ SO₂ Cl AR

F H H CF₃

CO₂ SO₂ SO₂ Cl AS

F H H CF₃

SO₂ SO₂ SO₂ Cl AT

F H H CF₃

SO₂ SO₂ SO₂ H AU

F H H CF₃

SO₂ SO₂ SO₂ Cl AV

OCH₃ H H CF₃

SO₂ SO₂ SO₂ Cl AW

OCH₃ H H CF₃

SO SO₂ SO₂ Cl AX

OCH₃ H H CF₃

CO₂ SO₂ SO₂ Cl AY

H H H CH₃

SO₂ SO₂ SO₂ OCF₃ AZ

H H H CF₃

SO₂ SO₂ SO₂ OCF₃ BA

H H H CF₃

SO₂ SO₂ SO₂ Cl BB

H H H CF₃

SO₂ SO₂ SO₂ H BC

H H H CH₃

SO₂ SO₂ SO₂ H BD

H H H CF₃

CO₂ SO₂ SO₂ OCF₃ BE

H H H CF₃

CO₂ SO₂ SO₂ Cl BF

H CH₃ CH₃ CF₃

SO₂ SO₂ SO₂ Cl BG

H CH₃ CH₃ CF₃

SO₂ SO₂ C═O CF₃ BH

H CH₃ CH₃ CF₃

SO₂ SO₂ C═O Cl BI

H CH₃ CH₃ CF₃

SO₂ SO₂ SO₂ CF₃ BJ

H CH₃ CH₃ H

SO₂ SO₂ CB CF₃ BK

H CH₃ CH₃ CF₃

CO₂ SO₂ SO₂ Cl BL

F H H CF₃

SO₂ SO₂ SO₂ CF₃ BM

OCH₃ H H CF₃

S SO₂ SO₂ Cl BN

F H H CF₃

CO₂ SO₂ SO₂ CF₃ BO

F H H CF₃

SO₂ SO₂ SO₂ Cl BP

OH H H CF₃

CO₂ SO₂ SO₂ Cl BQ

H H CH₃

CO₂ SO₂ SO₂ Cl BR

F H H CF₃

SO₂ SO₂ SO₂ Cl BS

H H CH₃

CO₂ CO₂ SO₂ Cl BT

CH₃ H H CF₃

SO₂ SO₂ C═O Cl BU

H H CF₃

CO₂ SO₂ SO₂ Cl BV

OH H H CH₃

CO₂ SO₂ SO₂ Cl BW

F H H CF₃

SO₂ SO₂ C═O Cl BX

C₃H₇ H H CF₃

CO₂ SO₂ SO₂ Cl BY

F H H CF₃

SO₂ SO₂ SO₂ Cl BZ

H H CF₃

CO₂ SO₂ SO₂ Cl CA

H H H CF₃

SO₂ SO₂ C═O Cl CB

H H H CF₃

SO₂ SO₂ SO₂ H CC

H H H CF₃

SO₂ SO₂ SO₂ Cl CD

H H H CF₃

SO₂ SO₂ C═O Cl CE

H H H CF₃

SO₂ SO₂ C═O OCF₂H CF

H H H CH₃

SO₂ SO₂ SO₂ H CG

H H H CF₃

SO₂ SO₂ C═O H CH

H H H CF₃

SO₂ SO₂ C═O OCH₃ CI

H H H C₂H₅

SO₂ SO₂ SO₂ OCF₃ CJ

H H H CH₃

SO₂ SO₂ SO₂ OCF₃ CK

H H H CF₃

SO₂ SO₂ SO₂ OCF₃ CL

H H H CF₃

SO₂ SO₂ C═O OCF₃ CM

H H H CF₃

SO₂ SO₂ C═O CF₃ CN

H H H CF₃

SO₂ SO₂ C═O OCF₃ CO

H H H CH₃

SO₂ SO₂ SO₂ Cl CP C₄H₉ H H H CH₃

SO₂ SO₂ SO₂ Cl CQ

H H H C₂H₅

CO₂ SO₂ SO₂ Cl CR CH₃ H H H CF₃

CO₂ SO₂ C═O H CS

H H H CF₃

CO₂ SO₂ SO₂ CF₃ CT

H H H CF₃

CB SO₂ C═O H CU

H H H CH₃

CB SO₂ SO₂ H CV Cl H H H CH₃

CB SO₂ SO₂ Br CW

H H H CH₃

CB SO₂ SO₂ H CX

F H H CF₃

CO₂ SO₂ C═O Cl CY H H H H CH₃

CB SO₂ SO₂ H CZ

H H H CF₃

SO₂ C═O SO₂ H DA

F H H CF₃

SO SO₂ SO₂ Cl DB

F H H CF₃

SO SO₂ SO₂ Cl DC

H H H CF₃

SO₂ CH₂ C═O OCF₃ DD CH₃ H O* O* H

CO₂ SO₂ CB H DE

H H H CH₃

CB SO₂ SO₂ H DF

H H H CH₃

CB SO₂ SO₂ H DG

H H H N(CH₃)₂

CO₂ SO₂ SO₂ Cl DH Br H H H CH₃

CB SO₂ SO₂ H DI CH₃ H H H CH₃

CB SO₂ SO₂ t-butyl DJ

F H H CF₃

CO₂ SO₂ SO₂ H DK

OCH₃ H H CF₃

SO₂ SO₂ SO₂ Cl DL

OC₂H₅ H H H

S SO₂ CB Cl DM

OCH₃ H H CH₃

SO₂ SO₂ SO₂ Cl DN

F H H CF₃

SO SO₂ SO₂ Cl DO

OC₂H₅ H H CF₃

SO₂ SO₂ SO₂ Cl DP

OCH₃ H H CH₃

SO₂ SO₂ SO₂ Cl DQ

F H H CF₃

SO₂ SO₂ SO₂ Cl DR

F H H CF₃

SO₂ SO₂ SO₂ Cl DS

F H H CF₃

SO₂ SO₂ SO₂ Cl DT CH₃ H H H CH₃

SO₂ SO₂ SO₂ Cl DU

H H H CF₃

SO₂ CH₂ SO₂ H

[0225] In a preferred embodiment, representative compounds of thepresent invention, or a pharmaceutically acceptable salt of thecompounds set forth in Table 2 below: TABLE 2

Cmp. R¹ R² R⁶ A L¹ X A

H CF₃

CO₂ Cl C

H CF₃

CO₂ Cl D

H CF₃

CO₂ H E

H CF₃

CO₂ Cl F

H CH₃

CO₂ Cl G

H CF₃

CO₂ Cl H i-propyl H CF₃

CO₂ Cl J

H CH₃

SO₂ OCH₃ L

H CH₃

SO₂ OCF₂H M

H CH₃

SO₂ OCF₃ N

H C₂H₅

SO₂ OCF₂H Q

H CF₃

SO₂ CF₃ AK

OCH₃ CH₃

CO₂ Cl AL

CH₃ CF₃

SO₂ Cl AM

CH₃ CH₃

SO₂ Cl AN

CH₃ CF₃

CO₂ Cl AO

H CF₃

SO₂ H AP

H CF₃

CO₂ OCH₃ AQ

F CF₃

SO₂ Cl AR

F CF₃

CO₂ Cl AS

F CF₃

SO₂ Cl AT

F CF₃

SO₂ H AU

F CF₃

SO₂ Cl AV

OCH₃ CF₃

SO₂ Cl AW

OCH₃ CF₃

SO Cl AX

OCH₃ CF₃

CO₂ Cl AZ

H CF₃

SO₂ OCF₃ BB

H CF₃

SO₂ H BD

H CF₃

CO₂ OCF₃ BE

H CF₃

CO₂ Cl DK

OCH₃ CF₃

SO₂ Cl DM

OCH₃ CH₃

SO₂ Cl DO

OC₂H₅ CF₃

SO₂ Cl DP

OCH₃ CH₃

SO₂ Cl EF

H CH₃

SO₂ OCH3 EG

H CH₃

SO₂ OH EH

F CF₃

SO₂ OCH3 EI

CH₃ CF₃

SO₂ H FG

H CF₃

SO₂ H FH

CH₃ CF₃

SO₂ H

Spectral Data for Selected Compounds in Table 2

[0226] Compound A

[0227]¹H NMR (300 MHz, CDCl₃) δ7.77 (d, J=8.4 Hz, 1H), 7.56 (dd, J=8.4,2.4 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 5.20 (t, J=6.3 Hz, 1H), 4.05 (s,2H), 3.90 (br d, J=12.3 Hz, 2H), 3.19 (t, J=6.6 Hz, 2H), 2.59 (dd,J=12.3, 2.4 Hz, 2H), 1.81 (br d, J=12.6 Hz, 2H), 1.52-1.68 (m, 1H),1.20-1.40 (m, 2H), 1.01 (s, 9H).

[0228] Compound C ¹H NMR (300 MHz, CDCl₃) δ7.75 (d, J=7.2 Hz, 1H), 7.60(dd, J=7.2, 2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 5.19 (t, J=6.3 Hz, 1H),3.85 (d, J=12.3 Hz, 2H), 3.19 (t, J=6.3 Hz, 2H), 2.55 (td, J=12.3, 2.4Hz, 2H), 2.04 (s, 6H), 1.80 (br d, J=12.9 Hz, 2H), 1.52-1.72 (m, 1H),1.22-1.44 (m, 2H).

[0229] Compound D ¹H NMR (300 MHz, CDCl₃) δ7.77 (d, J=7.8 Hz, 1H),7.50-7.65 (m, 2H), 7.44 (dd, J=7.8, 1.2 Hz, 1H), 5.15 (t, J=6.0 Hz, 1H),3.95 (br d, J=12.0 Hz, 2H), 3.17 (t, J=6.3 Hz, 2H), 2.56 (t, J=12.0 Hz,2H), 1.80 (d, J=12.0 Hz, 2H), 1.61 (s, 9H), 1.49-1.72 (m, 1H), 1.22-1.42(m, 2H).

[0230] Compound E ¹H NMR (300 MHz, CDCl₃) δ7.73 (d, J=8.6 Hz, 1H), 7.50(dd, J=8.6, 2.1 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 4.95 (t, J=6 Hz, 1H),3.93 (br d, J=12.3 Hz, 2H), 3.18 (t, J=6.3 Hz, 2H), 2.59 (td, J=12.3,2.4 Hz, 2H), 1.82 (br d, J=12.6 Hz, 2H), 1.61 (s, 9H), 1.19-1.42 (m,3H).

[0231] Compound F

[0232]¹H NMR (300 MHz, CDCl₃) δ7.72 (d, J=8.4 Hz, 1H), 7.50 (dd, J=8.4,2.3 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 4.26 (t, J=6.3 Hz, 1H), 3.92 (br d,J=12.4 Hz, 2H), 3.03 (t, J=6.3 Hz, 2H), 2.96 (s, 3H), 2.59 (td, J=12.4,2.3 Hz, 2H), 1.83 (br d, J=12.6 Hz, 2H), 1.61 (s, 9H), 1.50-1.64 (m,1H), 1.22-1.42 (m, 2H).

[0233] Compound G

[0234]¹H NMR (300 MHz, CDCl₃) δ7.74 (d, J=8.4 Hz, 1H), 7.51 (dd, J=8.4,2.1 Hz, 1H), 7.42 (d, J=2.1 Hz, 1H), 5.15 (m, 1H), 4.22 (quint, J=2.4Hz, 1H), 3.90 (br d, J=12.6 Hz, 2H), 3.17 (d, J=6.6 Hz, 2H), 2.57 (dd,J=12.6, 2.4 Hz, 2H), 1.81 (br d, J=12.9 Hz, 2H), 1.34-1.74 (m, 9H).

[0235] Compound H ¹H NMR (300 MHz, CDCl₃) δ7.74 (d, J=8.4 Hz, 1H), 7.53(dd, J=8.4, 2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 5.18-5.34 (m, 2H), 3.90(br d, J=12.6 Hz, 2H), 3.17 (d, J=6.6 Hz, 2H), 2.57 (dd, J=12.6, 2.4 Hz,2H), 1.81 (br d, J=12.9 Hz, 2H), 1.49-1.68 (m, 1H), 1.39 (d, J=6.3 Hz,6H), 1.20-1.40 (m, 2H).

[0236] Compound J ¹H NMR (300 MHz, CDCl₃) δ8.10-8.24 (m, 2H), 8.00 (d,J=9 Hz, 1H), 7.54-7.66 (m, 1H), 7.37(t, J=9 Hz, 1H), 7.17-7.22 (m, 1H);7.06-7.07 (m, 1H); 4.30-4.48 (m, 1H); 3.98 (s, 3H); 3.90-3.98 (m, 2H);2.97-3.04 (m, 2H); 2.95 (s, 3H); 2.60-2.76 (m, 2H); 1.72-1.86 (m, 2H);1.50-1.70 (m, 1H); 1.20-1.38 (m, 2H)

[0237] Compound L ¹H NMR (300 MHz, CDCl₃) δ8.22 (t, J=2.7 Hz, 1H), 7.97(td, J=7.7, 1.8 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.38-7.48 (m, 1H), 7.31(dd, J=8.7, 2.4 Hz, 1H), 7.18 (td, J=6.6, 1.2 Hz, 1H), 6.91 (td, J=8.8,1.2 Hz, 1H), 6.31 (t, J_(H-F)=54 Hz, 1H), 4.41 (t, J=6.3 Hz, 1H), 3.79(d, J=12.9 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H), 2.77 (s, 3H), 2.56 (td,J=12.9, 2.4 Hz, 2H), 1.63 (br d, J=10.8 Hz, 2H), 1.38-1.57 (m, 1H),1.02-1.20 (m, 2H).

[0238] Compound M

[0239]¹H NMR (300 MHz, CDCl₃) δ8.52 (s, 1H), 8.07-8.21 (m, 2H),7.57-7.68 (m, 2H), 7.38 (t, J=7.5 Hz, 1H), 7.09 (t, J=8.4 Hz, 1H), 4.58(t, J=6.3 Hz, 1H), 4.00 (d, J=12.7 Hz, 2H), 3.02 (t, J=6.7 Hz, 2H), 2.98(s, 3H), 2.78 (t, J=12.7 Hz, 2H), 1.82 (br d, J=10.2 Hz, 2H), 1.18-1.40(m, 3H).

[0240] Compound N ¹H NMR (300 MHz, CDCl₃) δ8.22 (t, J=2.4 Hz, 1H), 7.99(td, J=7.5, 1.5 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.38-7.45 (m, 1H), 7.30(dd, J=8.7, 1.8 Hz, 1H), 7.15 (td, J=7.8, 2.4 Hz, 1H), 6.90 (td, J=9.6,1.0 Hz, 1H), 6.55 (t, J_(H-F)=72 Hz, 1H), 4.32 (t, J=6.6 Hz, 1H), 3.78(d, J=12.5 Hz, 2H), 2.78-2.90 (m, 4H), 2.55 (td, J=12.5, 2.1 Hz, 2H),1.63 (br d, J=10.8 Hz, 2H), 1.38-1.54 (m, 1H), 1.17 (t, J=7.2 Hz, 3H),1.00-1.20 (m, 2H).

[0241] Compound Q

[0242]¹H NMR (300 MHz, CDCl₃) δ8.96 (s, 1H), 8.21 (d, J=7.5 Hz, 1H),8.17 (d, J=7.5 Hz, 1 H), 8.02 (d, J=7.5 Hz, 1H), 7.58-7.69 (m, 1H),7.32-7.42 (m, 1H), 7.09 (t, J=7.8 Hz, 1H), 6.33 (br s, 1H), 4.02 (br d,J=12.1 Hz, 2H), 3.30 (t, J=6.5 Hz, 2H), 2.80 (t, J=12.1 Hz, 2H),1.66-1.83 (m, 3H), 1.20-1.42 (m, 2H).

[0243] Comound AK ¹H NMR (300 MHz, CDCl₃) δ7.71 (d, J=8.3 Hz, 1H), 7.49(dd, J=8.7 Hz, 2.1 Hz, 1H), 7.39 (d, J=2.1 Hz, 1H), 4.37 (t, J=5.7 Hz,1H), 3.59 (m, 2H), 3.13 (d, J=4.9 Hz, 2H), 3.12 (s, 3H), 2.97 (s, 3H),2.93 (m, 2H), 1.92 (m, 2H), 1.60 (s, 9H), 1.57 (m, 2H).

[0244] Compound AL ¹H NMR (300 MHz, CD₃OD) δ8.54 (t, J=2 Hz, 1H), 8.08(td, J=8, 2 Hz, 1H), 8.00 (d, J=8 Hz, 1H), 7.92 (dd, J=8, 2 Hz, 1H),7.63-7.77 (m, 1H), 7.41 (t, J=8 Hz, 1H), 7.21 (t, J=8 Hz, 1H), 3.30-3.42(m, 2H), 3.10 (ddd, J=13, 11, 4 Hz, 2H), 2.83 (br s, 2H), 1.48-1.62 (m,2H), 1.23-1.41 (m, 2H), 0.89 (s, 3H).

[0245] Compound AM

[0246]¹H NMR (300 MHz, CDCl₃) δ8.66 (t, J=2 Hz, 1H), 8.15 (td, J=8, 2Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 7.57-7.66 (m,1H), 7.36 (t, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 4.29 (t, J=7 Hz,1H), 3.58 (ddd, J=14, 6, 6 Hz, 2H), 3.46 (d, J=7.5 Hz, 1H), 3.41 (d,J=7.5 Hz, 1H), 3.08 (ddd, J=14, 11, 4 Hz, 2H), 2.96 (s, 3H), 1.52-1.62(m, 2H), 1.21-1.36 (m, 2H), 0.98 (s, 3H).

[0247] Compound AN

[0248]¹H NMR (300 MHz, CDCl₃) δ7.74 (d, J=8 Hz, 1H), 7.54 (dd, J=8, 2Hz, 1H), 7.41 (d, J=2 Hz, 1H), 5.10 (br s, 1H), 3.52 (ddd, J=12, 6, 6Hz, 2H), 3.04-3.14 (m, 2H), 3.00 (ddd, J=12, 11, 4 Hz, 2H), 1.61 (s,9H), 1.40-1.62 (m, 4H), 0.97 (s, 3H).

[0249] Compound AO ¹H NMR (300 MHz, CDCl₃) δ8.25 (d, J=9.3 Hz, 1H), 8.03(dt, J=1.6 Hz, 7.0 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.51-7.60 (m, 2H),7.47 (b, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 7.05 (t,J=9.6 Hz, 1H), 5.6 (b, 1H), 3.95 (d, J=13 Hz, 2H), 3.19 (d, J=6.6 Hz,2H), 2.84 (t, J=11.5 Hz, 2H), 1.81 (d, J=13.3 Hz, 2H), 1.70 (m, 1H),1.35 (dt, J=4.0 Hz, 11.6 Hz, 2H)

[0250] Compound AP ¹H NMR (300 MHz, CDCl₃) δ7.71 (d, J=9 Hz, 1H), 7.00(dd, J=9, 2.7 Hz, 1H), 6.88 (dd, J=2.7 Hz, 1H), 5.16 (t, J=6 Hz, 1H),3.93 (br d, J=12 Hz, 2H), 3.90 (s, 3H), 3.19 (d, J=6.3 Hz, 1H), 3.17 (d,J=6.3 Hz, 1H), 2.56 (ddd, J=12.3, 12.1, 2.4 Hz, 2H), 1.80 (br d, J=11.7Hz, 2H), 1.61 (s, 9H), 1.50-1.61 (m, 1 H), 1.22-1.41 (m, 2H).

[0251] Compound AQ

[0252]¹H NMR (300 MHz, CDCl₃) δ8.66 (t, J=2.4 Hz, 1H), 8.07 (td, J=8,1Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.74 (dd, J=8.4, 2.4 Hz, 1H), 7.59-7.68(m, 1H), 7.37 (td, J=8, 1 Hz, 1H), 7.10 (td, J=8, 1 Hz, 1H), 5.07 (t,J=6.3 Hz, 1H), 3.81-3.97 (m, 2H), 3.45 (d, J=6.3 Hz, 1H), 3.38 (d, J=6.3Hz, 1H), 3.11 (ddd, J=10.5, 10.5, 3 Hz, 2H), 1.97-2.07 (m, 2H),1.62-1.88 (m, 2H).

[0253] Compound AR ¹H NMR (300 MHz, CDCl₃) δ7.71 (d, J=8.7 Hz, 1H), 7.51(dd, J=8.7, 2.1 Hz, 1H), 7.42 (d, J=2.1 Hz, 1H), 5.16 (t, J=6.8 Hz, 1H),3.78-3.88 (m, 2H), 3.44 (d, J=6.8 Hz, 1H), 3.37 (d, J=6.8 Hz, 1H), 2.94(ddd, J=11.2, 11.2, 3 Hz, 2H), 1.97-2.07 (m, 2H), 1.64-1.89 (m, 2H),1.62 (s, 9H).

[0254] Compound AS

[0255]¹H NMR (300 MHz, CDCl₃) δ8.69 (d, J=2.1 Hz, 1H), 8.50-8.55 (m,1H), 8.19 (d, J=8 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.94-8.05 (m, 1H), 7.77(dd, J=2.4, 8.0 Hz, 1H), 7.45-7.55 (m, 1H), 5.13 (t, J=6.6 Hz, 1H),3.83-3.93 (m, 2H), 3.41 (dd, J=6.0, 20 Hz, 2H), 3.01-3.11 (m, 2H),1.83-2.05 (m, 2H), 1.62-1.85 (m, 2H)

[0256] Compound AT ¹H NMR (300 MHz, CDCl₃) δ8.26 (d, J=8.8 Hz, 1H), 8.04(dt, J=1.8 Hz, 7.5 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.49-7.61 (m, 3H),7.38 (t, J=7.5 Hz, 1H), 7.29 (t, J=8.2 Hz, 1H), 7.06 (t, J=8.9 Hz, 1H),5.43 (t, J=6.3 Hz, 1H), 3.87 (d, J=15 Hz, 2H), 3.43 (dd, J=6.3 Hz, 20Hz, 2H), 3.2 (dt, J=2.8 Hz, 12.3 Hz, 2H), 2.0 (dt, J=2.9 Hz, 12.1 Hz,2H), 1.80 (m, 2H).

[0257] Compound AU ¹H NMR (300 MHz, CDCl₃) δ8.58 (dd, J=1.2 Hz, J=1.2Hz, 1H), 8.05 (dd, J=8.4 Hz, J=1.15 Hz, 1H), 7.76 (dd, J=8.4 Hz, J=2.2Hz, 1H), 7.48-7.6 (m, 1H), 5.34 (t, J=6.5 Hz, 2 H), 3.9 (dt, J=13.7 Hz,J=2.5 Hz, 2H), 3.4 (dd, J=20.5 Hz, J=6.3 Hz, 2H), 3.12 (dt, J=12.9 Hz,J=2.6 Hz, 2H), 2.04-1.91 (m, 2H), 1.88-1.6 (m,2H).

[0258] Compound AV ¹H NMR (300 MHz, CDCl₃) δ8.66 (t, J=2.3 Hz, 1H), 8.13(m, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.74 (dd, J=8.3, 2.2 Hz, 1H), 7.61 (m,1H), 7.36 (t, J=7.8 Hz, 1H), 7.09 (m, J=9.5 Hz, 1H), 5.17 (b, 1H), 3.69(m, 2H), 3.27 (d, J=2.9 Hz, 2H), 3.16 (s, 3H), 3.09 (m, 2H), 1.92 (m,2H), 1.57 (m, 2H).

[0259] Compound AW ¹H NMR (300 MHz, CDCl₃) δ8.37 (s, 1H), 7.83 (d, J=8.4Hz, 1H), 7.66 (dd, J=2.1 Hz, 8.4 Hz, 1H), 7.50 (m, 1H), 7.40 (m, 1H),7.25 (t, J=8.0 Hz, 1H), 7.16 (t, J=8.7 Hz, 1H), 5.00 (b, 1H), 3.65 (m,1H), 3.54 (m, 1H), 3.28 (t, J=6.6 Hz, 2H), 3.14 (s, 3H), 2.88 (m, 2H),1.94 (m, 2H), 1.60 (m, 2H).

[0260] Compound AX

[0261]¹H NMR (300 MHz, CDCl₃) δ7.72 (d, J=8.8 Hz, 1H), 7.49 (dd, J=8.6Hz, 2.1 Hz, 1H), 7.39 (d, J=2.1 Hz, 1H), 5.04 (d, 1H), 3.59 (m, 2H),3.25 (s, 2H), 3.12 (s, 3H), 2.94 (m, 2H), 1.91 (m, 2H), 1.59 (s, 9H),1.58 (m, 2H).

[0262] Compound AZ ¹H NMR (300 MHz, CDCl₃) δ8.52 (s, 1H), 8.15-8.25 (m,2H), 7.82 (d, J=8.7 Hz, 1H), 7.56-7.71 (m, 1H), 7.32-7.50 (m, 1H),7.02-7.19 (m, 1H), 5.07 (s, 1H), 4.01 (br d, J=12.9 Hz, 2H), 3.20 (t,J=6.3 Hz, 2H), 2.79 (td, J=12.9, 2.4 Hz, 2H), 1.83 (s, 2H), 1.22-1.50(m, 3H).

[0263] Compound BB ¹H NMR (300 MHz, CDCl₃) δ8.28 (dd, J=1 Hz, 8.6 Hz, 1H), 8 (td, J=2 Hz, 9 Hz, 2 H), 7.59 (td, J=1 Hz, 8 Hz, 1 H), 7.52 (td,J=1.4 Hz, 8 Hz, 1 H), 7.48 (d, J=1 Hz, 1 H), 7.33 (dt, J=1.2 Hz, 7.7 Hz,1 H), 6.86 (td, J=2.2 Hz, 9.2 Hz, 2 H), 5.17 (b, 1 H), 4.01 (d, J=13 Hz,2 H), 3.79 (s, 3 H), 3.23 (d, J=7 Hz, 2 H), 2.91 (dt, J=2.6 Hz, 13 Hz, 2H), 1.83 (d, J=13 Hz, 2 H), 1.72 (m, 1 H), 1.41 (dt, J=3.5 Hz, 13 Hz, 2H)

[0264] Compound BD ¹H NMR (300 MHz, CDCl₃) δ7.82 (d, J=8.2 Hz, 1H), 7.37(dd, J=8.2, 2.3 Hz, 1 H), 7.23 (d, J=2.3 Hz, 1H), 6.63 (br s, 1 H), 3.92(d, J=12.4 Hz, 2H), 3.24 (t, J=6.3 Hz, 2H), 2.60 (td, J=12.4, 2.3 Hz,2H), 1.78 (br d, J=12.6 Hz, 2H), 1.63 (s, 9H), 1.20-1.47 (m, 3H).

[0265] Compound BE ¹H NMR (300 MHz, CDCl₃) δ7.76 (d, J=7.2 Hz, 1H), 7.61(dd, J=7.2, 2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 5.19 (t, J=6.3 Hz, 1H),3.89 (d, J=12.3 Hz, 2H), 3.18 (t, J=6.3 Hz, 2H), 2.57 (td, J=12.3, 2.4Hz, 2H), 2.16 (s, 3H), 1.82 (br d, J=12.9 Hz, 2H), 1.50-1.71 (m, 1H),1.20-1.41 (m, 2H).

[0266] Compound DK ¹H NMR (300 MHz, CDCl₃) δ8.68 (d, J=2.26 Hz, 1H),8.51 (m, 1H), 8.18 (d, J=7.9 Hz, 1H), 7.98 (m, 2H), 7.76 (dd, J=8.4, 2.1Hz, 1H), 7.48 (m, 1H), 5.28 (b, 1H), 3.67 (m, 2H), 3.26 (s, 2H), 3.14(s, 3H), 3.04 (m, 2H), 1.90 (m, 2H), 1.54 (m, 2H).

[0267] Compound DM ¹H NMR (300 MHz, CDCl₃) δ8.66 (t, J=2.33 Hz, 1H),8.14 (td, J=7.5 Hz,1.8 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.74 (dd, J=8.6Hz, 2.3 Hz, 1H), 7.61 (m, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.09 (t, J=9.0Hz, 1H), 4.47 (t, J=5.7 Hz), 3.69 (m, 1H), 3.16 (s, 3H), 3.15 (d, J=6.3Hz, 2H), 3.09 (m, 2H), 2.99 (s, 3H), 1.93 (m, 2H), 1.57 (m, 2H).

[0268] Compound DO

[0269]¹H NMR (300 MHz, CDCl₃) δ8.66 (t, J=2.4 Hz, 1H), 8.14 (m, 1H),8.04 (d, J=8.6 Hz, 1H), 7.74 (dd, J=8.4 Hz, 2.3 Hz, 1H), 7.62 (m, 1H),7.36 (t, J=8.0 Hz, 1H), 7.10 (t, J=9.2 Hz, 1H), 5.03 (b, 1H), 3.68 (m,2H), 3.33 (q, J=7.1 Hz, 2H), 3.28 (s, 2H), 3.14 (m, 2H), 1.92 (m, 2H),1.58 (m, 2H), 1.19 (t, J=7.1 Hz, 3H).

[0270] Compound DP

[0271]¹H NMR (300 MHz, CDCl₃) δ8.69 (d, J=2.3 Hz, 1H), 8.52 (m, 1H),8.19 (d, J=8.0 Hz, 1H), 7.97 (m, 2H), 7.76 (dd, J=2.4 Hz, 8.6 Hz, 1H),7.48 (m, 1H), 4.46 (t, J=6.5 Hz, 1H), 3.68 (m, 2H), 3.15 (s, 3H), 3.13(d, J=6.1 Hz, 2H), 3.04 (m, 2H), 2.98 (s, 3H), 1.91 (m, 2H), 1.55 (m,2H).

[0272] Compound EG

[0273] 1H NMR (CDCl₃) δ7.99 (t, J=8 Hz, 1 H), 7.72 (d, J=9 Hz, 1 H),7.59 (s, 1H), 7.53 (m, 2 H), 7.32-7.19 (m, 2 H), 7.04 (t, J=9 Hz, 1 H),6.73 (d, J=8 Hz, 1 H), 6.42 (b, 1 H), 4.68 (m, 1 H), 3.89 (d, J=14 Hz, 2H), 3.0 (t, J=7 Hz, 2 H), 2.94 (s, 3 H), 2.81 (t, J=12 Hz, 2 H), 1.78(t, J=12 Hz, 2 H), 1.64 (b, 1 H), 1.28 (m, 2 H).

[0274] The compounds of the present invention exhibit anti-inflammatoryand/or immunomodulatory activity and are useful in the treatment ofvarious medical conditions including, e.g., rheumatoid arthritis,systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes,osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia,nephritis, psoriasis, allergy, inflammatory disorders of the lungs andgastrointestinal tract such as Crohn's disease, and respiratory tractdisorders such as reversible airway obstruction, asthma, chronicobstructive pulmonary disease (COPD) and bronchitis. This utility ismanifested as demonstrated by activity in the following assay.

[0275] Potential cannabinoid receptor ligands were screened for theability to compete with [³H] CP-55,940 for binding to recombinantcannabinoid receptors. Test compounds were serially diluted in DiluentBuffer (50 mM Tris pH 7.1, 1 mM EDTA, 3 mM MgCl₂, 0.1% BSA, 10% DMSO,0.36% methyl cellulose (Sigma M-6385)) from stocks prepared in 100%DMSO. Aliquots (10 μL) were transferred into 96-well microtiter plates.Membrane preparations of recombinant human cannabinoid CB2 receptor(Receptor Biology #RB-HCB2) or recombinant human cannabinoid CB1receptor (Receptor Biology #RB-HCB1) were diluted to 0.3 mg/mL inBinding Buffer (50 mM Tris pH 7.2, 1 mM EDTA, 3 mM MgCl₂, 0.1% BSA).Aliquots (50 μL) were added to each well of the microtiter plate. Thebinding reactions were initiated by addition of [³H] CP-55,940 (NewEngland Nuclear #NET 1051; specific activity=180 Ci/mmol) to each wellof the microtiter plate. Each 100 μl reaction mixture contained 0.48 nM[³H] CP-55,940, 15 μg membrane protein in binding buffer containing 1%DMSO and 0.036% methyl cellulose. Following incubation for 2 hours atroom temperature, the reactions were filtered through 0.5%polyethylenimine-coated GF/C filter plates (UniFilter-96, Packard) witha TomTec Mark 3U Harvester (Hamden, Conn.). The filter plate was washed5 times with binding buffer, rotated 1800, then re-washed 5 times withbinding buffer. Bound radioactivity was quantitated following additionof 30 μl of Packard Microscint 20 scintillant in a Packard TopCount NXTmicroplate scintillation counter. Non-linear regression analysis of theresulting data was performed using Prism 2.0b (GraphPad, San Diego,Calif.).

[0276] Compounds of the present invention were found to exhibit CB2receptor binding activity in the range of 0.1 to 1000 nM.

[0277] The present invention also relates to a pharmaceuticalcomposition comprising a compound of formula I of this invention and apharmaceutically acceptable carrier. The compounds of formula I can beadministered in any conventional dosage form known to those skilled inthe art. Pharmaceutical compositions containing the compounds of formulaI can be prepared using conventional pharmaceutically acceptableexcipients and additives and conventional techniques. Suchpharmaceutically acceptable excipients and additives include non-toxiccompatible fillers, binders, disintegrants, buffers, preservatives,anti-oxidants, lubricants, flavorings, thickeners, coloring agents,emulsifiers and the like. All routes of administration are contemplatedincluding, but not limited to, parenteral, transdermal, subcutaneous,intramuscular, sublingual, inhalation, rectal and topical.

[0278] Thus, appropriate unit forms of administration include oral formssuch as tablets, capsules, powders, cachets, granules and solutions orsuspensions, sublingual and buccal forms of administration, aerosols,implants, subcutaneous, intramuscular, intravenous, intranasal,intraocular, subcutaneous or rectal forms of administration.

[0279] When a solid composition is prepared in the form of tablets,e.g., a wetting agent such as sodium lauryl sulfate can be added tomicronized or non-micronized compounds of formula I and mixed with apharmaceutical vehicle such as silica, gelatin starch, lactose,magnesium stearate, talc, gum arabic or the like. The tablets can becoated with sucrose, various polymers, or other appropriate substances.Tablets can be treated so as to have a prolonged or delayed activity andso as to release a predetermined amount of active principle continuouslyor at predetermined intervals, e.g., by using ionic resins and the like.

[0280] A preparation in the form of gelatin capsules may be obtained,e.g., by mixing the active principle with a diluent, such as a glycol ora glycerol ester, and incorporating the resulting mixture into soft orhard gelatin capsules.

[0281] A preparation in the form of a syrup or elixir can contain theactive principle together, e.g., with a sweetener, methylparaben andpropylparaben as antiseptics, flavoring agents and an appropriate color.

[0282] Water-dispersible powders or granules can contain the activeprinciple mixed, e.g., with dispersants, wetting agents or suspendingagents, such as polyvinylpyrrolidone, as well as with sweeteners and/orother flavoring agents.

[0283] Rectal administration may be provided by using suppositorieswhich may be prepared, e.g., with binders melting at the rectaltemperature, for example cocoa butter or polyethylene glycols.

[0284] Parenteral, intranasal or intraocular administration may beprovided by using, e.g., aqueous suspensions, isotonic saline solutionsor sterile and injectable solutions containing pharmacologicallycompatible dispersants and/or solubilizers, for example, propyleneglycol or polyethylene glycol.

[0285] Thus, to prepare an aqueous solution for intravenous injection,it is possible to use a co-solvent, e.g., an alcohol such as ethanol ora glycol such as polyethylene glycol or propylene glycol, and ahydrophilic surfactant such as Tween® 80. An oily solution injectableintramuscularly can be prepared, e.g., by solubilizing the activeprinciple with a triglyceride or a glycerol ester.

[0286] Topical administration can be provided by using, e.g., creams,ointments or gels.

[0287] Transdermal administration can be provided by using patches inthe form of a multilaminate, or with a reservoir, containing the activeprinciple and an appropriate solvent.

[0288] Administration by inhalation can be provided by using, e.g., anaerosol containing sorbitan trioleate or oleic acid, for example,together with trichlorofluoromethane, dichlorofluoromethane,dichlorotetrafluoroethane or any other biologically compatiblepropellant gas; it is also possible to use a system containing theactive principle, by itself or associated with an excipient, in powderform.

[0289] The active principle can also be formulated as microcapsules ormicrospheres, e.g., liposomes, optionally with one or more carriers oradditives.

[0290] Implants are among the prolonged release forms which can be usedin the case of chronic treatments. They can be prepared in the form ofan oily suspension or in the form of a suspension of microspheres in anisotonic medium.

[0291] The daily dose of a compound of formula I for treatment of adisease or condition cited above is about 0.001 to about 100 mg/kg ofbody weight per day, preferably about 0.001 to about 10 mg/kg. For anaverage body weight of 70 kg, the dosage level is therefore from about0.1 to about 700 mg of drug per day, given in a single dose or 2-4divided doses. The exact dose, however, is determined by the attendingclinician and is dependent on the potency of the compound administered,the age, weight, condition and response of the patient.

[0292] Compounds of the present invention can be can be used incombination with disease modifying antirheumatic agents described hereinabove, the administration and dosage of such agents is as according tothe schedule listed in the product information sheet of the approvedagents, in the Physicians Desk Reference (PDR) as well as therapeuticprotocols well known in the art.

[0293] Compounds of the present invention can be can be used incombination with H1 antagonists described herein above, theadministration and dosage of such agents is as according to the schedulelisted in the product information sheet of the approved agents, in thePhysicians Desk Reference (PDR) as well as therapeutic protocols wellknown in the art.

[0294] Compounds of the present invention can be can be used incombination with compounds useful in the treatment of multiple sclerosisdescribed herein above, the administration and dosage of such agents isas according to the schedule listed in the product information sheet ofthe approved agents, in the Physicians Desk Reference (PDR) as well astherapeutic protocols well known in the art.

[0295] Compounds of the present invention can be can be used incombination with compounds useful in the treatment of psoriasisdescribed herein above, the administration and dosage of such agents isas according to the schedule listed in the product information sheet ofthe approved agents, in the Physicians Desk Reference (PDR) as well astherapeutic protocols well known in the art.

[0296] Compounds of the present invention can be can be used incombination with compounds useful in the treatment of psoriasisdescribed herein above, the administration and dosage of such agents isas according to the schedule listed in the product information sheet ofthe approved agents, in the Physicians Desk Reference (PDR) as well astherapeutic protocols well known in the art.

[0297] It will be apparent to those skilled in the art that theadministration of the agents used in combination with the compounds ofthe present invention can be varied depending on the disease beingtreated and the known effects of the agents on that disease. Also, inaccordance with the knowledge of the skilled clinician, the therapeuticprotocols (e.g. dosage amounts and times of administration) can bevaried in view of the observed effects of the administered agents on thepatients, and in view of the observed responses of the disease to theadministered agents.

[0298] The following examples illustrate the preparation of some of thecompounds of the invention and are not to be construed as limiting theinvention disclosed herein. Alternate mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

EXAMPLE I

[0299]

[0300] Step 1. A mixture of 4-(trifluoroacetamidomethyl)piperidiniumtrifluoroacetate (16.1 g, 49.6 mmol) and triethylamine (15 mL, 11 g, 109mmol) in CH₂Cl₂ (100 mL) was cooled to 0° C. and a solution ofp-chlorobenzenesulfonyl chloride (11.5 g, 54.5 mmol) in CH₂Cl₂ (100 mL)was added dropwise by cannula over 5 min. The ice bath was removed andthe reaction was allowed to proceed for 18 h at rt. The reaction mixturewas poured into water. The layers were separated and the aq. layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over MgSO₄, and filtered. The solvent was evaporated toafford 16.8 g (96%) of Compound 1.

[0301] Step 2. n-BuLi (9.8 mL, 1.7 M in hexane, 17 mmol) was addeddropwise over 10 min to a solution of Compound 1 (4.92 g, 14.0 mmol) inTHF (100 mL) at −78° C. The resulting orange-yellow solution was stirredat −78° C. for 30 min. A solution of di-t-butyl dicarbonate (3.7 g, 17mmol) in THF (40 mL) was added by cannula and the reaction mixture wasstirred at −78° C. for 5 h. The reaction mixture was partitioned betweenwater (200 mL) and EtOAc (200 mL). The aq. layer was extracted againwith EtOAc. The combined organic layers were washed with brine, driedover MgSO₄, and filtered. The solvent was evaporated to yield 5.54 g(82%) of Compound 2.

[0302] Step 3. Compound 2 (5.54 g, 11.4 mmol) was dissolved in MeOH (110mL). A solution of potassium carbonate (11.1 g, 80.0 mmol) in water (100mL) was added and the reaction mixture was stirred at rt for 12 h. Thesolvent was removed under reduced pressure and the resulting white pastewas diluted with water (˜20 mL) and extracted with EtOAc (3×100 mL). Thecombined organic extracts were washed with brine, dried over MgSO₄, andfiltered. The solvent was evaporated to yield 3.41 g (84%) of Compound3.

[0303] Step 4. Compound E A solution of Compound 3 (3.14 g, 8.80 mmol)and triethylamine (2.5 mL, 1.8 g, 18 mmol) in CH₂Cl₂ (90 mL) was cooledto −78° C. and a solution of trifluoromethanesulfonic anhydride (1.6 mL,2.7 g, 9.7 mmol) in CH₂Cl₂ (10 mL) was added dropwise over 5 min. Thereaction mixture was stirred at −78° C. for 1 h, then poured intosaturated aq NaHCO₃ solution. The organic layer was withdrawn and theaq. layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried over MgSO₄, and filtered. Solvent wasevaporated to afford an oil. Further purification by sgc (4:1hexane-EtOAc) afforded 2.545 g (56%) of Compound 4 (E).

EXAMPLE II

[0304]

[0305] Compound I. Compound 4, from Example I, step 4 (65 mg, 0.12 mmol)was dissolved in MeOH (1 mL) and palladium(II) hydroxide on carbon (4mg, 20 wt % Pd, 0.006 mmol) was added. The reaction mixture was stirredunder hydrogen atmosphere (ambient pressure) for 15 h, then filteredthrough a short pad of silica gel, eluting with EtOAc. The solvent wasremoved to provide a clear film, which was purified by sgc (2:1hexane-EtOAc) to yield 55 mg (91%) of Compound 5(I).

EXAMPLE III

[0306]

[0307] Step 1. To a solution of Compound 1 (34.6 g, 93 mmol) in MeOH(1800 mL) was added a solution of potassium carbonate (90 g, 650 mmol)in water (700 mL). The solution was stirred at rt for 18 h. The solventwas evaporated and the residue was partitioned between EtOAc (500 mL)and water (1000 mL). The organic layer was withdrawn, and the aq. layerwas extracted further with EtOAc (5×200 mL). The combined organic layerswere dried over MgSO₄ and then filtered. Solvent was removed underreduced pressure to yield 21.5 g (80%) of Compound 6.

[0308] Step 2. A solution of Compound 6 above (21.5 g, 77.6 mmol) andtriethylamine (32 mL, 24 g, 233 mmol) in CH₂Cl₂ (350 mL) was cooled to−78° C. and a solution of trifluoromethanesulfonic anhydride (22 g, 78mmol) in CH₂Cl₂ (250 mL) was added dropwise over 2 h. The reactionmixture was stirred for a further 2 h at −78° C., then diluted withCH₂Cl₂ (500 mL). The organic solution was washed with 1 N HCl, water,and brine, then dried over MgSO₄, and filtered. Solvent was evaporatedto afford 28.3 g (87%) of Compound 7.

[0309] Step 3. n-BuLi (4.7 mL, 2.5 M in hexane, 12 mmol) was addeddropwise over 10 min to a solution of Compound 7 (2.33 g, 5.55 mmol) inTHF (50 mL) at −78° C. The resulting solution was stirred at −78° C. for30 min. A solution of bis(2-fluorophenyl) disulfide (1.4 g, 5.5 mmol) inTHF (40 mL) was added by cannula and the reaction mixture was stirred at−78° C. for 5 h, and then allowed to warm to rt over ˜12 h. The reactionmixture was neutralized with saturated aq NaHSO₄ solution and waspartitioned between water (200 mL) and EtOAc (200 mL). The aq. layer wasextracted again with EtOAc. The combined organic layers were washed withbrine, dried over MgSO₄, and filtered. The solvent was evaporated to asolid. After purification by sgc (2:1 hexane-EtOAc), 2.52 g (83%) ofCompound 8 was obtained.

[0310] Step 4. Compound BA Compound 8 (1.42 g, 2.59 mmol) was dissolvedin dry CH₂Cl₂ (25 mL) and cooled to 0° C. Solid MCPBA (3.58 g, ˜50 wt %.1.79 g, 10.4 mmol) was added portionwise. The resulting suspension wasstirred at 0° C. for 5 min and at rt for 18 h. The reaction mixture wasdiluted with CH₂Cl₂ (˜500 mL) and washed successively with saturated aqNaHCO₃, water, and brine, dried over MgSO₄, and filtered. Evaporativeremoval of the solvent afforded a solid that was purified by sgc (2:1hexanes-EtOAc) to yield 1.34 g (89%) of Compound 9.

[0311] Compound 2: Compound 1 (4.82 g, 30.6 mmol) was dissolved in HOAc(60 mL) at 0° C. Then HCl (con. 40 mL) was added followed by addition ofNaNO₂ (6.33 g, 92 mmol) in H₂O (40 mL). This mixture was stirred at 0°C. for 30 min. Meanwhile in another container SO₂ was bubbled into HOAc(100 mL) at 0° C. for 40 min. CuCl (cat.) was added to this mixturefollowed by addition of the diazonium salt. The reaction was stirred at0° C. for 1.5 h. The reaction mixture was poured into ice (500 g) andstirred for 1.5 h. The solid was collected by suction filtration. Thesolid was dissolved in CH₂Cl₂ (50 mL) and washed by brine. The organiclayer was separated and dried over Na₂SO₄, and concentrated to drynessto give 4 g (54%) crude compound 2 as a yellow solid.

[0312] Compound 4: Compound 2(2.41 g, 10 mmmol) was dissolved in CH₂Cl₂(10 mL) at room temperature. Compound 3 (2.1 g, 10 mmol) was addedfollowed by addition of triethylamine (5.6 mL, 40 mol). The mixture wasstirred at rt for 0.5 h. It was extracted with brine (30 mL). Theorganic layer was dried over Na₂SO₄, and concentrated to dryness. Thecrude product was purified with via sgc (33% EtOAc/hexanes) to give 3.2(84%) compound 4 as a white powder.

[0313] Compound 5: Compound 4 (3.2 g, 8.44 mmol) was suspended in anammonia solution (30 mL; 7N in MeOH) and was stirred at rt for 24 h. Thesolvent was removed under reduced pressure to afford 2.96 g (100%)compound 5 as white solid.

[0314] Compound 6: Borane-methyl sulfide complex (2.85 mL, 10 M in THF,28.5 mmol) was added to a suspension of Compound 5 (2.96 g, 8.44 mmol)in THF (30 mL). The reaction mixture was stirred at reflux for 3 h, thencooled to 0° C. Concentrated HCl (2 mL) was added dropwise. The pH ofthe solution was adjusted tp neutrality was addition of 1 M of NaOH (˜15mL). The mixture was diluted with EtOAc (˜30 mL) and water (100 mL). Theorganic layer was separated and dried over Na₂SO₄ and concentrated todryness. This material (1.86 g, 5.52 mmol) was dissolved in CH₂Cl₂ (30mL) and cooled to −78° C. Et₃N (1.92, 13.9 mmol) was added followed bythe addition of TFAA (0.78 mL, 5.52 mmol). The reaction mixture wasstirred for 1.5 h before warming up to 0° C. Brine (15 mL) was added andthe product was extracted with CH₂Cl₂ (50 mL). The organic layer wasdried over Na₂SO₄ and concentrated to dryness. The crude product waspurified via sgc (50% EtOAc/hexanes) to give 507 mg (16%) compound 6 asa white solid.

[0315] Compound 7: In a flame dried flask under N₂ blanket, compound 6(507 mg, 1.17 mmol) was dissolved in dry THF (30 mL) and cooled to −78°C. n-Butyl lithium (2.0 M in hexanes, 1.23 mL, 2.46 mmol) was addedfollowed after 45 min by pyridine disulfide (258 mg, 1.17 mmol). Thecold bath was removed after 2 h and the reaction mixture was allowed towarm to rt over 45 minutes then quenched with aq NH₄Cl. EtOAc (30 mL)was added to dilute the reaction. The reaction mixture was washed withbrine (100 mL×2). The organic layer was dried over Na₂SO₄ and thenconcentrated to dryness. The crude material was dissolved in CH₂Cl₂ (30mL) and HOAc (1 mL) and cooled to 0° C. MCPBA (2.4 g, ca 1.38 mmol) wasadded. The ice bath was removed and the reaction mixture was stirred atrt overnight. Aqueous NaHCO₃ (200 mL) and CH₂Cl₂ were added and thelayers were separated. The organic layer was washed with aq NaHSO₃,NaHCO₃, H₂O, and brine then dried with Na₂SO₄. The crude product ispurified by sgc (50% EtOAc/hexanes) to give 210 mg (31%) of compound 7as a white solid.

[0316] Compound 8: Compound 7 (205 mg, 0.36 mmol) was dissolved indioxane (8 mL) at room temperature. LiOH (1.0 M, 8.0 mL, 8.0 mmol) wasadded and the mixture was stirred at room temperature for overnight. Thesolvent was removed and CH₂Cl₂ (15 mL) and brine (15 mL) was added andthe layers were separated. The aqueous layer was extracted withadditional CH₂Cl₂ (15 mL) and the combined organic layers were driedover Na₂SO₄ and concentrated to dryness to give compound 8 (170 mg, 99%)as a white powder.

[0317] Compound 9A: Compound 8 (76 mg, 0.16 mmol) was dissolved inCH₂Cl₂ (15 mL) and cooled to −78° C. Et₃N (40 mg, 0.4 mmol) was addedfollowed by the addition of trifluoromethanesulfonic anhydride (45 mg,0.16 mmol). The reaction mixture was stirred for 30 min before warmingup to 0° C. Brine (15 mL) was added and the product was extracted withCH₂Cl₂ (15 mL). The organic layer was dried over Na₂SO₄ and concentratedto dryness. The crude product was purified via PTLC (33% EtOAc/hexanes)to give 47 mg (47%) Compound 9A as a white solid.

EXAMPLE IV

[0318]

[0319] Step 1. A mixture of 4-(trifluoroacetamidomethyl)piperidiniumtrifluoroacetate (500 mg, 1.54 mmol) and triethylamine (470 μL, 343 mg,3.39 mmol) in CH₂Cl₂ (1 mL) was cooled to 0° C. and a solution of2-naphthalenesulfonyl chloride (350 mg, 1.54 mmol) in CH₂Cl₂ (0.5 mL)was added in one portion by cannula. The ice bath was removed and thereaction was allowed to proceed for 16 h at rt. The reaction mixture wasdiluted with CH₂Cl₂ and washed successively with 1 N HCl, water, andbrine. The organic phase was dried over MgSO₄ and filtered. Evaporationof the solvent afforded an oil that was then purified by sgc (1:1hexanes-EtOAc) to give 532 mg (86%) of Compound 10.

[0320] Step 2. Compound 10 (299 mg, 0.745 mmol) was dissolved in MeOH (4mL) and THF (4 mL) and a solution of potassium carbonate (721 mg, 5.22mmol) in water (2 mL) was added. The solution was stirred at rt for 15h. The solvent was evaporated under reduced pressure and the aq. residuewas partitioned between EtOAc (˜50 mL) and water (˜25 mL). The organiclayer was washed with brine, dried over MgSO₄, and filtered. Evaporationof the solvent provided 125 mg (55%) of product.

[0321] Step 3. A solution of Compound 11 (62 mg, 0.202 mmol) andtriethylamine (42 μL, 31 mg, 0.303 mmol) in CH₂Cl₂ (200 μL) was cooledto 0° C. and trifluoromethanesulfonic anhydride (34 μL, 57 mg, 0.202mmol) was added. The ice bath was removed and the reaction was allowedto proceed for 12 h at rt. The reaction mixture was diluted with CH₂Cl₂and washed successively with 1 N HCl, water, and brine. The organicphase was dried over MgSO₄ and filtered. Evaporation of the solventafforded a solid that was then purified by sgc (1:1 hexanes-EtOAc) togive 25 mg (29%) of Compound 12.

EXAMPLE V

[0322]

[0323] Step 1. A solution of Compound 1 (10.0 g, 28.5 mmol) in THF (150mL) was cooled to −78° C. and MeLi (22 mL, 1.0 M in THF-cumene, 31 mmol)was added dropwise over ˜5 min. n-BuLi (20 mL, 2.5 M in hexane, 31 mmol)was added dropwise over ˜5 min, and the resulting solution was stirredat −78° C. for 30 min. Sulfur powder (1.095 g, 34 mmol) was added in oneportion. The reaction mixture was stirred at −78° C. for 1 h and then atrt for 18 h. The reaction mixture was poured into saturated aq. NH₄Clsolution (˜500 mL) and diluted with EtOAc (500 mL). The aq layer wasextracted with another portion of EtOAc (˜250 mL). The combined extractswere washed with brine, dried over MgSO₄, and filtered. Removal ofsolvent gave a syrup. Purification by sgc (1:1 hexanes-EtOAc) afforded7.23 g (61%) of Compound 13.

[0324] Step 2. To a suspension of sodium hydride (78 mg, 60% dispersionin oil, 2.0 mmol) in THF (2 mL) at 0° C. was added, dropwise by cannulaover 5 min, a solution of Compound 13 (628 mg, 1.51 mmol) in THF (13mL). The solution was stirred at 0° C. for 30 min. lodomethane (122 mL,278 mg, 2.0 mmol) was added in one portion and the reaction mixture wasstirred at 0° C. for 5 min and then at rt for 15 h. The reaction mixturewas diluted with EtOAc and poured into brine. The organic layer waswithdrawn, dried over MgSO₄, and filtered. Evaporation of the solventprovided an oil. Purification by sgc (3:1 hexanes-EtOAc) gave 432 mg(67%) of Compound 14 as a viscous syrup.

[0325] Step 3. To a solution of Compound 14 (424 mg, 0.983 mmol) inCH₂Cl₂ (5 mL) at 0° C. was added MCPBA (615 mg, ˜70 wt %, 431 mg, 2.50mmol) in one portion. The reaction mixture was stirred at 0° C. for 1min, then at rt for 16 h. The reaction mixture was diluted with EtOAc,then washed successively with saturated aq. NaHCO₃ and brine. Theorganic layer was dried over MgSO₄ and filtered. Evaporation of thesolvent, followed by purification of the resulting oil by sgc (5:3hexanes-EtOAc) gave 272 mg (60%) of Compound 15.

[0326] Step 4. Solid potassium carbonate (342 mg, 2.47 mmol) was addedto a solution of Compound 15 (229 mg, 0.494 mmol) in MeOH (5 mL) andwater (1.5 mL). The reaction mixture was stirred at rt for 16 h, thendiluted with EtOAc (40 mL), and washed with water (20 mL). The organicphase was washed with brine, dried over MgSO₄, and filtered. Evaporationof the solvent afforded 148 mg (83%) of Compound 16.

[0327] Step 5. Compound DT A solution of Compound 16 (66 mg, 0.18 mmol)and triethylamine (33 μL, 27 mg, 0.24 mmol) in CH₂Cl₂ (450 μL) wascooled to 0° C. and MsCl (18 μL, 27 mg, 0.24 mmol) was added dropwise.The solution was stirred at 0° C. for 2 min and then at rt for 2 h. Thereaction mixture was diluted with EtOAc and washed successively withwater and brine. The organic phase was dried over MgSO₄ and filtered.Removal of the solvent afforded a solid that was then purified by sgc(1:1 hexanes-EtOAc) to yield 59 mg (74%) of Compound 17(DT).

EXAMPLE VI

[0328]

[0329] Step 1. To a solution of ethyl isonipecotate (50 g, 0.318 mol) inCH₂Cl₂ (150 mL) at 0° C. was added a solution of di-t-butyl dicarbonate(73 g, 0.334 mol) in CH₂Cl₂ (150 mL) over 15 min. The ice bath wasremoved and the reaction mixture was stirred at rt for 12 h. The solventwas evaporated to yield a liquid. Subsequent purification by sgc (4:1hexanes-Et₂O) gave 80 g (98%) of Compound 18.

[0330] Step 2. To a solution of LDA (233 mL, 2.0 M inTHF/heptane/ethylbenzene, 0.466 mol) in THF (300 mL) at 0° C. was added,dropwise over 1.0 h, a solution of Compound 18 (100 g, 0.389 mol) in THF(˜400 mL). The solution was stirred at 0° C. for 30, and thentransferred by cannula to a pre-cooled (0° C.) solution ofN-fluorobenzenesulfonimide (153 g, 0.485 mol) in dry THF (˜600 mL). Thereaction mixture was stirred at 0° C. for 30 min, and then at rt for 18h. The total solvent volume was reduced to approximately one third, andEtOAc (˜1 L) was added. The solution was washed successively with water,0.1 N aq. HCl, water, saturated aq. NaHCO₃, and brine. The organic layerwas dried over MgSO₄, filtered, and concentrated under reduced pressureto yield a crude liquid. Separation by sgc (6:1 hexanes-EtOAc) gave 93.5g (87%) of Compound 19.

[0331] Step 3. To Compound 19 (182 g, 0.66 mol) was added HCl (800 mL,4.0 M in dioxane). The solution was stirred at rt for 12 h, after whichthe solvent was removed under reduced pressure to afford a solid. Thesolid was redissolved in CH₂Cl₂ (1 L) and triethylamine (275 mL, 200 g,1.97 mol) was added. The reaction mixture was cooled to 0° C., and asolution of p-chlorobenzenesulfonyl chloride (139 g, 0.66 mol) in CH₂Cl₂(500 mL) was added over 10 min. The ice bath was removed and thereaction was allowed to proceed at rt for 3 h. The reaction mixture wasdiluted with CH₂Cl₂ (1 L) and washed successively with 1 N HCl, water,and brine. The organic layer was dried over MgSO₄ and then filtered.Evaporation of the solvent afforded 163 g (71% over two steps) ofCompound 20.

[0332] Step 4. Compound 20 (30 g, 86 mmol) was suspended in an ammoniasolution (1 L; 7 N in MeOH) and was stirred at rt for 24 h. The solventwas removed under reduced pressure to afford a solid. CH₂Cl₂ (500 mL)was added, and then removed under reduced pressure to yield 28.7 g(100%) of Compound 21.

[0333] Step 5. Borane-methyl sulfide complex (25 mL, 10 M in THF, 250mmol) was added to a suspension of Compound 21 (15.0 g, 46.7 mmol) inTHF (200 mL). The reaction mixture was stirred at reflux for 3 h, thencooled to 0° C. THF (500 mL) was added. Concentrated hydrochloric acid(13 mL) was added dropwise over 45 min. The pH of the solution wasadjusted to neutrality via addition of 0.5 M NaOH solution (˜350 mL).The mixture was diluted with EtOAc (˜500 mL) and water (1 L). Theorganic layer was separated and the aq. layer extracted again with EtOAc(2×500 mL). The combined extracts were washed with brine (1×1 L), driedover MgSO₄, and filtered. The solvent was evaporated to give 10.6 g(74%) of Compound 22.

[0334] Step 6. To a solution of Compound 22 (10.6 g, 34.6 mmol) andtriethylamine (15 mL, 11 g, 104 mmol) in CH₂Cl₂ (300 mL) at −78° C. wasadded, dropwise over 30 min, a solution of trifluoromethanesulfonicanhydride (5.8 mL, 9.8 g, 35 mmol) in CH₂Cl₂ (100 mL). The solution wasstirred at −78° C. for 3 h, then diluted with CH₂Cl₂ (300 mL), andwashed successively with 1 N HCl, water, and brine. The organic phasewas dried over MgSO₄ and filtered. Removal of the solvent under reducedpressure afforded a solid that was purified by sgc (3:1 hexanes-EtOAc)to give 6.3 g (42%) of Compound 23.

[0335] Step 7. Compound AR To a solution of Compound 23 (1.6 g, 3.7mmol) in THF (30 mL) at −78° C. was added n-BuLi (3.2 mL, 2.5 M inhexane, 8.0 mmol). The reaction mixture was stirred at −78° C. for 1 h,after which a solution of di-t-butyl dicarbonate (1.6 g, 7.3 mmol) inTHF (10 mL) was added. The reaction was allowed to proceed for 4 h.Dilute HCl (50 mL, 1.0 M) was added, and the solution was extracted withEtOAc. The organic phase was washed successively with 1 N NaHCO₃ andbrine, dried over MgSO₄, and filtered. Removal of solvent afforded aclear paste that was purified by sgc (3:1 hexanes-EtOAc) to give 1.28 g(65%) of Compound 24 (AR).

EXAMPLE VII

[0336]

[0337] Step 1. To a solution of 1-(t-butoxycarbonyl)-4-cyanopiperidine(1.05 g, 5.00 mmol) in THF (15 mL) at −78° C. was added a solution ofLDA (3.0 mL, 2.0 M in THF/cumene/ethylbenzene, 6.0 mmol). The resultingsolution was stirred at −78° C. for 30 min. lodomethane (0.4 mL, 6 mmol)was added. The reaction mixture was allowed to warm to rt, and wasstirred at rt for 18 h. The reaction mixture was diluted with EtOAc andwashed successively with 1 N HCl, 1 M aq NaHCO₃, and brine. The organiclayer was dried over Na₂SO₄ and filtered. Removal of solvent afforded anoily residue that was purified by sgc (4:1 hexanes-EtOAc) to give 1.05 g(94%) of Compound 25.

[0338] Step 2. A mixture of Compound 25 (1.00 g, 4.46 mmol) and Rh/Al₂O₃catalyst (300 mg, 5 wt %, 0.14 mmol) in methanolic ammonia solution (15mL, ˜3.5 N NH₃ in MeOH) was shaken under hydrogen atmosphere (˜40 psi).The solution was filtered through a silica gel pad, and the filtrate wasconcentrated to give 1.00 g (98%) of Compound 26.

[0339] Step 3. To a solution of Compound 26 (2.0 g, 8.8 mmol) andtriethylamine (5.0 mL, 3.6 g, 36 mmol) in CH₂Cl₂ at 0° C. was added TFAA(1.5 mL, 2.2 g, 11 mmol). The reaction mixture was allowed to warm tort, and was stirred for 18 h. The reaction mixture was diluted withCH₂Cl₂ and washed successively with 1 N HCl, water, 1 M aq NaHCO₃, andbrine. The organic layer was dried over Na₂SO₄ and filtered. Removal ofthe solvent gave 2.8 g (100%) of Compound 27.

[0340] Step 4. A mixture of Compound 27 (2.8 g, 8.8 mmol) and hydrogenchloride solution (20 mL, 4.0 M in dioxane) was stirred at rt for 15 h.Evaporation of the solvent gave 2.3 g (100%) of Compound 28.

[0341] Step 5. To a solution of Compound 28 (1.30 g, 5.00 mmol) andtriethylamine (5.0 mL, 3.6 g, 36 mmol) was added p-chlorobenzenesulfonylchloride (1.06 g, 5.02 mmol). The reaction mixture was stirred at rt for18 h, then diluted with CH₂Cl₂, and washed successively with 1 N HCl, 1M aq NaHCO₃, and brine. The organic layer was dried over Na₂SO₄ andfiltered. Evaporation of the solvent afforded a solid that was thenpurified by sgc (0.5% MeOH in CH₂Cl₂) to give 1.8 g (90%) of Compound29.

[0342] Step 6. To a solution of Compound 29 (420 mg, 1.06 mmol) in THF(10 mL) at −78° C. was added n-BuLi (1.5 mL, 1.6 M in hexanes, 2.4mmol). The solution was stirred at −78° C. for 30 min. A solution ofdi-t-butyl dicarbonate (220 mg, 1.01 mmol) in THF (2 mL) was added. Thereaction mixture was allowed to warm to rt, and was stirred for 18 h.The reaction mixture was diluted with EtOAc and washed with water andbrine, dried over Na₂SO₄, and filtered. Evaporation of the solvent gavea crude solid that was then purified by sgc (3:1 hexanes-EtOAc) to give530 mg (100%) of Compound 30.

[0343] Step 7. To a solution of Compound 30 (530 mg, 1.06 mmol) in MeOH(20 mL) was added a solution of potassium carbonate (1.5 g, 11 mmol) inwater (8 mL). The reaction mixture was stirred at rt for 18 h. Thesolvent was evaporated and the residue was partitioned between EtOAc andwater. The aq. layer was extracted further with EtOAc. The combinedextracts were washed with brine, dried over Na₂SO₄, and filtered.Evaporation of the solvent gave 350 mg (87%) of Compound 31.

[0344] Step 8. Compound AN To a solution of Compound 31 (300 mg, 0.75mmol) and triethylamine (2 mL, 1.5 g, 14 mmol) in CH₂Cl₂ (10 mL) at −78°C. was added a solution of trifluoromethanesulfonic anhydride (0.15 mL,0.25 g, 0.089 mmol) in CH₂Cl₂ (5 mL). The reaction mixture was stirredat −78° C. for 2 h, then diluted with CH₂Cl₂, and washed successivelywith 1 N HCl, 1 M aq. NaHCO₃, and brine. The organic layer was driedover MgSO₄ and filtered. Evaporation of the solvent yielded a solid thatwas purified by sgc (3:1 hexane-EtOAc) to give 270 mg (67%) of Compound32 (AN).

EXAMPLE VIII

[0345]

[0346] Step 1. Benzyl chloride (62.7 g, 0.496 mol) and diethanolamine(167.1 g, 1.589 mol) were dissolved in ethanol (115 mL, Pharmco 190proof) and heated to 100° C. The reaction mixture was stirred for 68 hat 100° C. then allowed to cool to rt. Water (200 mL), brine (200 mL),and CH₂Cl₂ (300 mL) were added and the layers were separated. Theaqueous layer was extracted with 100 mL of CH₂Cl₂. The combined organiclayers were washed with brine and dried with MgSO₄. Approximately halfthe solvent was evaporated and hexanes (200 mL) was added. The solventswere evaporated under reduced pressure. The resulting oil was left undervacuum overnight to give 106 g of an oil. Additional hexanes (250 mL)was added, followed by enough CH₂Cl₂ to bring the oil into solution. Thesolvents were evaporated to give 103 g of an oil. ¹H NMR indicated thatthis was the desired product, mixed with traces of ethanol. It was usedin the next step without additional purification.

[0347] Step 2. Compound 33 (103 g, 0.528 mol) was dissolved in1,2-dichloroethane (1050 mL) and added to a 3-necked, 3 L round-bottomflask equipped with a stir bar, addition funnel, and reflux condenser.The flask was placed in an oil bath and thionyl chloride (90 mL, 1.23mol) was added dropwise via addition funnel over 50 min. The flask waskept under N₂ flow, with the exhaust gases bubbled through aq. NaOH.During the addition of the thionyl chloride, the reaction mixture washeated to 50° C.—(gas evolution). Once the addition was complete, thereaction mixture was stirred at 60° C. for 1 h and at 70-80° C. for 3 h.The heat was turned off, and the reaction mixture was left stirringovernight. The reaction mixture was concentrated to dryness underreduced pressure. 141.3 g of Compound 34 was obtained. This material wasused in the next step without further purification.

[0348] Step 3. A 3-necked, 2 L round-bottom flask was flame dried underN₂ flow and allowed to cool to rt. Compound 34 (21.4 g, 79.6 mmol),anhydrous THF (245 mL), and cyclopropyl acetonitrile (7.4 g, 91 mmol)were added. The flask was reblanketed with N₂ and cooled in an ice-waterbath. Sodium bis(trimethylsilyl)amide (133 mL, 0.5 M in THF, 266 mmol)was added via addition funnel over 1 h. After the addition of the basewas complete, additional anhydrous THF was added (250 mL) and thereaction mixture was stirred for 3 h at 0° C. Water (150 mL) was addedfollowed by EtOAc. The layers were separated. The aqueous layer wasextracted with EtOAc and the combined organic layer was washed withbrine and dried with MgSO₄. The solvents were evaporated under reducedpressure to give 38.7 g of an oil. The crude product was purified viasgc using 0-2% MeOH/CH₂Cl₂ as the mobile phase. 5.12 g of Compound 35was obtained.

[0349] Step 4. In a Parr shaker bottle, Raney Nickel (1 teaspoon—Aldrich50%) was washed with absolute ethanol, which was decanted off.Methanolic ammonia (60 mL—7N) was added, followed by Compound 35 (1.5 g,6.2 mmol). The bottle was shaken under 28 psi of hydrogen at rtovernight—(28 psi=0.1 mol). The flask was recharged with 26 psi of H₂and shaken at rt for 3 h and 15 min. The resulting material was filteredthrough a pad of Celite®, which was rinsed with MeOH. The filtrate wasconcentrated to give an oil which was purified via sgc using 5:95MeOH/CH₂Cl₂ as the mobile phase, followed by 3:97 MeOH(NH₃)/CH₂Cl₂.Approximately 0.5 g of starting material and 0.9 g of Compound 36 wereisolated.

[0350] Step 5. Compound 36 (0.8 g, 3.3 mmol) was dissolved intriethylamine (1 mL) and CH₂Cl₂ (17 mL), placed under N₂ blanket, andcooled to −78° C. Trifluoromethanesulfonic anhydride (0.65 mL, 1.09mmol) was added. The reaction mixture was stirred at −78° C. for 3 h.MeOH was added (10 mL) and the Dry Ice bath was removed. The solventswere evaporated and the crude reaction mixture was purified via sgcusing a 2%-5% MeOH/CH₂Cl₂ gradient as the mobile phase. 1.15 g ofCompound 37 was obtained.

[0351] Step 6. Compound 37 (1.11 g, 2.94 mmol) was dissolved in1,2-dichloroethane (14 mL) and α-chloroethyl chloroformate (0.335 mL,3.1 mmol) was added. The reaction mixture was placed under N₂ blanketand heated to 80° C. The reaction mixture was stirred at 80° C. for 1.5h. The heat was turned off, and the reaction mixture was stirred at rtover the weekend. Additional α-chloroethyl chloroformate (0.250 mL) wasadded and the reaction mixture was stirred at 80° C. for 2 h. Thereaction mixture was allowed to cool to rt, then concentrated todryness. MeOH (50 mL) was added and the reaction mixture was refluxedovernight under N₂ blanket. The reaction mixture was concentrated todryness and purified via sgc using a 1.5%-10% MeOH/CH₂Cl₂ gradient.0.627 g of a foam was isolated and identified as the desired Compound38.

[0352] Step 7. Compound 38 (115 mg, 0.401 mmol), 4-chlorobenzenesulfonylchloride (120 mg, 0.569 mmol), N,N-dimethylaminopyridine (40 mg, 0.327),and tributylamine (200 μL, 0.839 mmol) were dissolved in CH₂Cl₂ (2 mL)and left stirring over the weekend at rt. The reaction mixture wasdiluted with CH₂Cl₂ and washed with 1.0 M aq. NaHSO₄ and brine. Theorganic layer was dried with MgSO₄ and concentrated to give 0.36 g of anoil. The crude product was purified via sgc using 20-25% EtOAc/hexanesas the mobile phase. 115 mg of Compound 39 was obtained.

[0353] Step 8. Compound BZ Compound 39 (81 mg, 0.175 mmol) was added toa flame dried Schlenk flask equipped with a stir bar. Anhydrous THF (1.5mL) was added and the flask was blanketed with N₂. The flask was placedin a Dry Ice/IPA bath and a solution of n-BuLi in hexanes (155 μL, 0.387mmol) was added. The reaction mixture was stirred at −78° C. for 1 h and15 min. Di-t-butyl dicarbonate (108 mg, 0.495 mmol) was added and thereaction mixture was left stirring overnight. The reaction mixture wasquenched with 1.0 M, pH 7.0 phosphate buffer and diluted with EtOAc. Thelayers were separated and the organic layer was washed with water andbrine, then dried with MgSO₄. Evaporation of the solvent afforded anoil. The crude product was purified via sgc to give 0.04 g of Compound40 (BZ).

EXAMPLE IX

[0354]

[0355] Step 1. 1-(t-Butoxycarbonyl)-4-methylenepiperidine (0.5 g, 2.6mmol) was stirred in 3:1 CH₂Cl₂-TFA (15 mL) at rt for 3 h. The reactionmixture was concentrated under vacuum to give Compound 41 as an oil.

[0356] Step 2. Compound 41 (1.55 g, 7.94 mmol) was then dissolved inCH₂Cl₂ (50 mL) and the solution was cooled to 0° C. Triethylamine (4.43mL, 31.8 mmol) and 4-chlorobenzenesulfonyl chloride (2.01 g, 9.53 mmol)were added and the resulting solution was stirred rt for 1.5 h. Waterwas added and the mixture was extracted with CH₂Cl₂ (20 mL). The organiclayer was dried over Na₂SO₄ and concentrated to dryness. The crudematerial was purified by sgc (10% EtOAc in hexanes) to give 1.05 g (51%)of Compound 42.

[0357] Step 3. In a flame dried flask under N₂ blanket, Compound 42(0.31 g, 1.2 mmol) was dissolved in dry THF (50 mL) and cooled to −78°C. n-BuLi (0.69 mL, 1.90 M solution in hexanes, 1.3 mmol) was added, andthe mixture was stirred at −78° C. for 40 min. Di-t-butyl dicarbonate(0.75 g, 3.4 mmol) was added to the reaction mixture, which was stirredat −78° C. for 1.5 h. The reaction mixture was slowly warmed to rt.Water was added to quench the reaction. The reaction mixture wasextracted with EtOAc (3×20 mL). The organic layer was dried over Na₂SO₄and concentrated to dryness to give 0.42 g (100%) of crude product,which could be used in the subsequent reaction without furtherpurification. A small portion of the crude product (35 mg) was purifiedvia sgc (10% EtOAc in hexanes) to give 31 mg of Compound 43.

[0358] Step 4. Compound 43 (1.22 g, 3.27 mmol) was dissolved in CH₂Cl₂(30 mL). MCPBA (1.41 g, 8.18 mmol) was added and the solution wasstirred overnight at rt. The reaction mixture was diluted with CH₂Cl₂,and washed with aq. NaHSO₃ and aq. NaHCO₃. The organic layers werecombined, dried over Na₂SO₄ and concentrated. The crude material waspurified via sgc (25% EtOAc in hexanes) to give 1.25 g (20%) of Compound44.

[0359] Step 5. Compound 44 (0.52 g, 1.3 mmol) was dissolved in1,4-dioxane (20 mL) and water (2 mL), and NaN₃ (0.26 g, 4.0 mmol) wasadded. The solution was heated overnight at reflux. The solvent wasevaporated under reduced pressure and the residue was taken up by waterand extracted with EtOAc (3×10 mL). The organic layers were combined anddried with Na₂SO₄, Evaporation of the solvent yielded Compound 45 (100%yield). This material was used in the next step without furtherpurification.

[0360] Step 6. Compound 45 (0.30 g, 0.69 mmol) was dissolved in THF (20mL). Sodium hydride (67 mg, 2.1 mmol) and iodomethane (0.174 mL. 2.1mmol) were added successively at rt. The resulting mixture was stirredovernight at rt. Water was added. The mixture was extracted with EtOAc(3×10 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to dryness. The crude material was purified via sgc (25%EtOAc in hexanes) to give 81 mg (26%) of Compound 46.

[0361] Step 7. Compound 46 (47 mg, 0.11 mmol) was dissolved in THF (5mL) and water (1 mL). Triphenylphosphine (55 mg, 0.21 mmol) was addedand the resulting mixture was stirred overnight at rt. Water was addedand the mixture was extracted with EtOAc (3×25 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated to dryness. The crudematerial was purified via sgc (10% 7N NH₃/MeOH solution in EtOAc) togive 25 mg (50%) of Compound 47.

[0362] Step 8. Compound AX Compound 47 (25 mg, 0.060 mmol) was dissolvedin CH₂Cl₂ (5 mL). Triethylamine (16.6 μL, 0.063 mmol) was added. Thesolution was cooled to −78° C. Triflic anhydride (10.5 μL) was addeddropwise. The reaction mixture was stirred at −78° C. for 1.5 h. Thesolvent was evaporated and the crude material purified by PTLC plate(25% EtOAc-hexanes) to give 22 mg (80%) of Compound 48 (AX).

EXAMPLE X

[0363]

[0364] Step 1. Compound 45 (0.19 g, 0.44 mmol) was dissolved in EtOAc(15 mL). Lindlar's catalyst (palladium, 5 wt % in calcium carbonate,poisoned with lead; 0.19 g) was added. The reaction mixture was shakenon a Parr apparatus under hydrogen atmosphere (52 psi) for 48 hrs. Thereaction mixture was filtered and the solvent was evaporated. The crudeproduct was purified via sgc to give 50 mg (28%) of Compound 49.

[0365] Step 2. Compound BP Compound 49 (48 mg, 0.12 mmol) was dissolvedin CH₂Cl₂ (5 mL). NEt₃ (33.0 μL, 0.237 mmol) was added. The mixture wascooled to −78° C. Trifluoromethanesulfonic anhydride (19.9 μL, 0.12mmol) was added and the reaction mixture was stirred for 1.5 h. Thesolvent was removed and the resulting crude material purified by PTLC(50% EtOAc in hexanes) to give 37.3 mg (67%) of Compound 50 (BP).

EXAMPLE XI

[0366]

[0367] Step 1. In a flame dried flask under N₂ blanket, Indole (5.0 g,43 mmol) was dissolved in THF (50 mL) and cooled to −78° C. A solutionof n-BuLi (1.6 M in hexanes, 29 mL, 47 mmol) was added over 15 min. Theresulting anion precipitated as a solid. The reaction mixture was warmed0° C. and stirred for 1 h before being cooled to −78° C. again. Asolution of 2-fluorobenzenesulfonyl chloride (9.1 g, 47 mmol) in THF (30mL) was added over 20 min. The reaction mixture was allowed to warmslowly to rt and was then stirred overnight at rt. The reaction mixturewas poured into 2% aq. NaHCO₃ (120 mL). The aq. layer was extracted withEt₂O (4×50 mL). The combined organic layers were washed with 2% aq.NaHCO₃ (30 mL), H₂O (2×75 mL) and brine (2×50 mL). The organic phase wasdried over Na₂SO₄ and concentrated to dryness. The crude product waspurified via sgc (5-8% EtOAc in hexanes) to give 11.6 g (98%) ofCompound 51.

[0368] Step 2. In a flame dried flask under N₂ blanket, Compound 51(1.74 g, 6.3 mmol) was dissolved in dry THF (30 mL) and cooled to −78°C. n-BuLi (1.84 M in hexanes, 3.4 mL, 6.3 mmol) was added and thereaction mixture was stirred for 50 min. SO₂ was bubbled slowly into thereaction vessel for 1 h. The reaction was warmed to rt. The reactionmixture was concentrated to 5 mL. Ice-cold hexanes (200 mL) was added,and precipitation of a solid occurred. The solid was collected byfiltration and was washed with cold hexanes. This solid was dissolved inCH₂Cl₂ (200 mL) at rt. NCS (0.93 g, 7.0 mmol) was added and the reactionwas stirred overnight. The mixture was washed with brine and the organiclayer was dried over Na₂SO₄ and concentrated to dryness. The crudeproduct was purified via sgc (9% EtOAc in hexanes) to give 800 mg (34%)of Compound 52.

[0369] Step 3. Compound AT Compound 52 (170 mg, 0.46 mmol) was dissolvedin CH₂Cl₂ (20 mL) at rt.4-Fluoro-4-(trifluoromethanesulfonamidomethyl)piperidiniumtrifluoroacetate (344 mg, 0.91 mmol) and triethylamine (92 mg, 0.92mmol) were added successively. The mixture was stirred for 4 h. Thereaction mixture was extracted with brine (30 mL). The organic layer wasdried over Na₂SO₄, and concentrated to dryness. The crude product waspurified by PTLC (33% EtOAc in hexanes) to give 136 mg (50%) of Compound53 (AT).

[0370] Compound 53A:

[0371] Compound 2: Compound 1 (1 g, 6.79 mmol) was dissolved in CH₂Cl₂(5 mL). NaOH (50%, 4 mL) was added followed by addition of2-fluorophenylsulphonyl chloride (1.6 g, 8.22 mmol) andtetrabutylammonium hydrogensulfate (cat.). The reaction mixture wasstirred at room temperature overnight. The aqueous layer was thenremoved, and the organic layer was dried over Na₂SO₄ and concentrated todryness. The crude product was purified via PTLC (10% EtOAc/hexanes) togive 2 g (97%) of compound 2 as a white solid.

[0372] Compound 3: In a flame dried flask under N₂ blanket, compound 2(2.0 g, 6.55 mmol) was dissolved in dry TFA (30 mL) and cooled to −78°C. A solution of n-butyl lithium (2.04 M in hexanes, 3.3 mL, 6.6 mmol)was added and the reaction mixture was stirred for 45 min. SO₂ wasbubbled in the reaction vessel at a slow rate for 45 min. The reactionwas warmed to room temperature. The reaction mixture was concentrated to5 mL. Ice cold hexanes (200 mL) was added, and precipitation occurred.The solid was collected by filtration and it was washed by cold hexanes.This solid was dissolved in CH₂Cl₂ (200 mL) at room temperature. NCS(1.05 g, 7.87 mmol) was added and the reaction was stirred overnight.The mixture was washed with brine and the organic layer was dried overNa₂SO₄, and concentrated to dryness. The crude product was purified viasgc (9% EtOAc/hexanes) to give 780 mg (30%) compound 3 as a light brownsolid.

[0373] Compound 4A: Compound 3 (100 mg, 0.25 mmol) was dissolved inCH₂Cl₂ (10 mL) at room temperature. Compound 4 (100 mg, 0.33 mmol) wasadded followed by addition of triethylamine (63 mg, 0.62 mmol). Themixture was stirred at rt overnight. It was extracted with brine (30mL). The organic layer was dried over Na₂SO₄, and concentrated todryness. The crude product was purified with preparative TLC plate (50%EtOAc/hexanes) to give 78 mg (56%) compound 4A as a white powder.

[0374] Compound 53A: Compound 4A (78 mg, 0.14 mmol) was dissolved inCH₂Cl₂ (10 mL) at 0° C. BBr₃ (1.0 M in CH₂Cl₂, 1 mL, 1 mmol) was added.The reaction mixture was slowly warmed up to rt and stirred overnight.The mixture was washed with brine and the organic layer was dried overNa₂SO₄, and concentrated to dryness. The crude product was purified viasgc (33% EtOAc/hexanes) to give 58 mg (78%) Compound 53A as a whitesolid.

EXAMPLE XIa

[0375]

[0376] Compound 2: Compound 1 (3 g, 0.026 mol) was dissolved in DMF (150mL), and cooled to 0° C. NaH (dry, 95%, 0.97 g, 0.038 mol) was added,and the reaction was stirred for 15 min. A solution of 2-fluorophenyldisulphide (6.5 g, 0.026 mol) in DMF (5 mL) was added, and the reactionwas allowed to proceed at r.t. overnight. The reaction was quenched withH₂O. Solvent was removed. CH₂Cl₂ was added to dilution the reactionmixture. The organics were extracted with brine (50 ml×2) and H₂O (50ml×2). The organic layer was dried over Na₂SO₄ and concentrated todryness. The crude product was purified via (10% EtOAc/hexanes) to give5.33 g (85%) of compound 2 as a white solid.

[0377] Compound 3: Compound 2 (2.1 g, 8.63 mmol) was dissolved in THF(35 mL). NaH (dry, 95%, 1.04 g, 43 mmol) was added, and the reaction wasstirred for 15 min. CH₃I (4.1 mL, 43 mmol) was added and the reactionwas stirred at rt overnight. H₂O was added to quench the reaction. EtOAc(20 mL) was added to dilute the reaction mixture. It was washed withbrine (40 mL×2). The organic layer was dried and concentrated to give2.2 g (99%) compound 3 as a white solid.

[0378] Compound 4: In a flame dried flask under N₂ blanket, compound 3(2.2 g, 8.6 mmol) was dissolved in dry THF (30 mL) and cooled to −78° C.A solution of LDA (1.4 M in cyclohexanes, 4.65 mL, 6.51 mmol) was addedand the reaction mixture was stirred for 20 min. SO₂ was bubbled in thereaction for 20 min. It was slowly warmed up to rt. The reaction mixturewas concentrated to dryness. The crude material was dissolved in CH₂Cl₂(5 mL). Cold hexane was added and precipitation occurred. The solid wascollected by filtration and it was washed by cold hexanes. The materialwas dissolved in CH₂Cl₂ (40 mL). NCS (2.3 g, 17.2 mmol) was added and itwas stirred at rt overnight. The reaction mixture was washed with brine(100 mL×2). The organic layer was dried over Na₂SO₄ and thenconcentrated to dryness to give crude compound 4 1.55 g (100%).

[0379] Compound 5: Compound 4 (0.83 g, 2.3 mmol) was dissolved in CH₂Cl₂(30 mL) at room temperature. Compound i (0.76 g, 2.3 mmol) was addedfollowed by addition of triethylamine (0.82 mL, 5.87 mmol). The mixturewas stirred at rt overnight. It was extracted with brine (30 mL). Theorganic layer was dried over Na₂SO₄, and concentrated to dryness. Thecrude product was dissolved in CH₂Cl₂ (40 mL) and cooled to 0° C. MCPBA(3.24 g, ca 13.2 mmol) was added. The ice bath was removed and thereaction mixture was stirred at rt overnight. Aqueous NaHCO₃ (200 mL)and CH₂Cl₂ were added and the layers were separated. The organic layerwas washed with aq NaHSO₃, NaHCO₃, H₂O, and brine then dried withNa₂SO₄. The crude product is purified by sgc (33% EtOAc/hexanes) to give0.57 g (44%) of compound 5 as a white solid.

[0380] Compound 6: Compound 5 (0.57 g, 1.01 mmol) was dissolved indioxane (4 mL) at room temperature. LiOH (1.0 M, 4.0 mL, 4.0 mmol) wasadded and the mixture was stirred at room temperature for overnight. Thesolvent was removed and CH₂Cl₂ (15 mL) and brine (15 mL) was added andthe layers were separated. The aqueous layer was extracted withadditional CH₂Cl₂ (15 mL) and the combined organic layers were driedover Na₂SO₄ and concentrated to dryness to give compound 6 0.44 g (92%).

[0381] Compound 7: Compound 6 (70 mg, 0.15 mmol) was dissolved in CH₂Cl₂(15 mL) and cooled to −78° C. Et₃N (0.053 mL, 0.38 mmol) was addedfollowed by the addition of trifluoromethanesulfonic anhydride (42 mg,0.15 mmol). The reaction mixture was stirred for 30 min before warmingup to 0° C. Brine (15 mL) was added and the product was extracted withCH₂Cl₂ (50 mL). The organic layer was dried over Na₂SO₄ and concentratedto dryness. The crude product was purified via PTLC (33% EtOAc/hexanes)to give 40 mg (45%) compound 7 as a white solid.

EXAMPLE XII

[0382]

[0383] Step 1. Indole-2-carboxylic acid (1.0 g, 6.2 mmol) and4-(trifluoroacetamidomethyl)piperidinium trifluoroacetate (2.2 g, 6.8mmol) were dissolved in CH₂Cl₂ (15 mL). HOBT (1.1 g, 8.1 mmol), EDCl(1.6 g, 8.1 mmol) and triethylamine (815 mg, 8.1 mmol) were added andthe mixture was stirred overnight at rt. The crude mixture was washedwith brine (2×15 mL). The organic layer was dried over Na₂SO₄ andconcentrated to dryness. The crude product was purified by sgc (EtOAc)to give 1.36 g (62%) of Compound 54.

[0384] Step 2. Compound 54 (1.0 g, 2.8 mmol) was dissolved in MeOH (10mL) at rt. NaOH (1.0 M, aq., 10 mL, 10.0 mmol) was added and the mixturewas stirred at rt for 4 h. The solvent was removed and CH₂Cl₂ (30 mL)and brine (30 mL) were added and the layers were separated. The aq.layer was extracted with additional CH₂Cl₂ (15 mL) and the combinedorganic layers were dried over Na₂SO₄ and concentrated to dryness togive 670 mg (100%) of Compound 55.

[0385] Step 3. Compound 55 (105 mg, 0.40 mmol) was dissolved in 1:1CH₂Cl₂-THF(20 mL). BOC-ON (100 mg, 0.40 mmol) and DMAP (catalyticamount) were added and the reaction mixture was stirred overnight at rt.The mixture was then washed with brine, and the organic layer was driedover Na₂SO₄ and concentrated to dryness. The crude product was purifiedby PTLC (50% EtOAc in hexanes) to give 144 mg (99%) of Compound 56.

[0386] Step 4. Compound 56 (140 mg, 0.39 mmol) was dissolved in CH₂Cl₂(5 mL). NaOH (1.0 M, aq., 5 mL), 2-fluorobenzenesulfonyl chloride (76mg, 0.39 mmol), and tetrabutylammonium hydrogen sulfate (catalyticamount) were added successively. The reaction mixture was stirredovernight at rt. The aq. layer was then removed, and the organic layerwas dried over Na₂SO₄ and concentrated to dryness. The crude product waspurified by PTLC (4% MeOH(NH₃) in CH₂Cl₂) to give 44 mg (22%) ofCompound 57.

[0387] Step 5. Compound CZ Compound 57 (40 mg, 0.078 mmol) was stirredin 3:1 CH₂Cl₂-TFA (4 mL) at rt for 30 min. The solvent was removed andthe crude material was dried under vacuum. This material was dissolvedin CH₂Cl₂ (15 mL) and cooled to −78° C. Trifluoromethanesulfonicanhydride (22 mg, 0.078 mmol) and triethylamine (31 mg, 0.31 mmol) wereadded successively. The reaction mixture was stirred at −78° C. for 1.5h, allowed to warm slowly to rt, and was stirred for an additional 1 h.The reaction mixture was washed with brine (15 mL). The organic layerwas dried over Na₂SO₄ and concentrated to dryness. The crude product waspurified by PTLC (50% EtOAc in hexanes) to give 14 mg (33%) of Compound58 (CZ).

EXAMPLE XIII

[0388]

[0389] Step 1. Lithium aluminum hydride (0.82 g, 22 mmol) was stirred inTHF (0.4 mL) at 0° C. A solution of ethyl indole-2-carboxylate (2.0 g,10 mmol) in THF (13 mL) was added dropwise. The reaction mixture wasslowly warmed up to rt and was stirred for 30 min. It was then cooled to0° C. Water (2 mL), NaOH (1 N, aq., 5 mL), and water (6 mL) were addedsuccessively. The mixture was stirred at rt for 15 min, then filteredthrough Celite® and washed with 10:1 CH₂Cl₂-MeOH (150 mL). The filtratewas washed with brine. The organic layer was dried over Na₂SO₄ andconcentrated to give 1.55 g (99%) of Compound 59.

[0390] Step 2. Compound 59 (1.5 g, 10 mmol) was dissolved in CH₂Cl₂ (30mL) at rt. Manganese dioxide (85%, 7.5 g, 73 mmol) was added and themixture was stirred at rt for 4 h. Another portion of manganese dioxide(85%, 6.0 g, 59 mmol) was added and the mixture was stirred for another0.5 h. The reaction mixture was filtered through Celite®. The Celite®pad was washed with 10:1 CH₂Cl₂:MeOH (250 mL). The filtrate wasconcentrated to dryness to give 1.22 g (82%) of Compound 60.

[0391] Step 3. Compound 60 (1.0 g, 6.9 mmol) was dissolved in CH₂Cl₂ (20mL). NaOH (1.0 M, aq., 10 mL), 2-fluorobenzenesulfonyl chloride (1.48 g,7.59 mmol), and tetrabutylammonium hydrogen sulfate (catalytic amount)were added successively. The reaction mixture was stirred at rt for 3 h.The aq. layer was removed, and the organic layer was dried over Na₂SO₄,then concentrated to dryness. The crude product was purified sgc (25%EtOAc in hexanes) to give 951 mg (46%) of Compound 61.

[0392] Step 4. Compound 61 (200 mg, 0.66 mmol) and4-(trifluoroacetamidomethyl) piperidinium trifluoroacetate (214 mg, 0.66mmol) were dissolved in CH₂Cl₂ (20 mL) at rt. Titanium tetrachloride(1.0 M in CH₂Cl₂, 0.34 mL, 0.34 mmol) was added followed by addition oftriethylamine (0.30 mL, 0.64 mmol). The reaction mixture was stirredovernight at rt. Sodium cyanoborohydride (125 mg, 1.99 mmol) in MeOH (1mL) was added and the reaction mixture was stirred at rt for 2 h. Thereaction mixture was washed with brine (40 mL), and the organic layerwas separated, then dried over Na₂SO₄ and concentrated to dryness. Thecrude material was purified by PTLC (33% EtOAc in hexanes) to give 92 mg(25%) of Compound 62.

[0393] Step 5 Compound 62 (87 mg, 0.18 mmol) was dissolved in1,4-dioxane (2 mL) at rt. LiOH (1.0 M, aq., 2 mL, 2.0 mmol) was addedand the mixture was stirred at rt for 4 h. The solvent was removed andCH₂Cl₂ (30 mL) and brine (30 mL) were added. The layers were separated.The aq. layer was extracted with additional CH₂Cl₂ (15 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated to dryness togive 70 mg (100%) of Compound 63.

[0394] Step 6. Compound DU Compound 63 (50 mg, 0.12 mmol) was dissolvedin CH₂Cl₂ (10 mL) and cooled to −78° C. Trifluoromethanesulfonicanhydride (36 mg, 0.12 mmol) was added followed by addition oftriethylamine (25 mg, 0.25 mmol). The reaction mixture was stirred at−78° C. for 45 min. The reaction mixture was washed with brine (15 mL).The organic layer was dried over Na₂SO₄ and concentrated to dryness. Thecrude product was purified by PTLC (33% EtOAc in hexanes) to give 43 mg(65%) of Compound 64 (DU).

EXAMPLE XIV

[0395]

[0396] Step 1. Cerium(III) chloride heptahydrate (25.5 g, 68.4 mmol)powder was stirred under vacuum (<0.1 mm Hg) at 145° C. for 18 h. Thesolid was allowed to cool to rt. THF (120 mL) was added and the solidwas stirred at rt for 2 h. The suspension was cooled to −78° C. MeLi (45mL, 1.4 M in Et₂O, 63 mmol) was added dropwise over 30 min. The reactionmixture was stirred −78° C. for 30 min. A solution of1-(t-butoxycarbonyl)-4-cyanopiperidine (4.35 g, 20.7 mmol) in THF (15mL) was introduced by cannula, and the reaction was allowed to proceedat −78° C. for 4.5 h. Conc. ammonium hydroxide (40 mL) was added and thereaction mixture was allowed to warm to rt. CH₂Cl₂ (100 mL) was addedand the mixture was stirred at rt for 1 h, then filtered through aCelite® pad. The Celite® pad was washed with CH₂Cl₂ (3×50 mL). Thecombined filtrates were concentrated under reduced pressure to afford5.0 g (99%) of Compound 65.

[0397] Step 2. To a solution of Compound 65 (5.0 g, 20.7 mmol) andtriethylamine (10 mL, 7.3 g, 72 mmol) in CH₂Cl₂ (100 mL) at 0° C. wasadded TFAA (3.0 mL, 4.5 g, 21 mmol). The reaction mixture was allowed towarm to rt, and was stirred for 18 h. The reaction mixture was dilutedwith CH₂Cl₂ and washed successively with water, 1 M aq NaHCO₃, andbrine. The organic layer was dried over Na₂SO₄ and filtered. Removal ofthe solvent gave a crude solid that was purified by sgc (0.5% MeOH inCH₂Cl₂) to give 5.8 g (83%) of Compound 66.

[0398] Step 3. A mixture of Compound 66 (5.0 g, 14.8 mmol) and hydrogenchloride solution (100 mL, 4.0 M in dioxane) was stirred at rt for 18 h.Evaporation of the solvent gave 4.0 g (99%) of Compound 67.

[0399] Step 4. To a solution of Compound 67 (500 mg, 1.82 mmol) andtriethylamine (1.5 mL, 1.1 g, 11 mmol) was added p-chlorobenzenesulfonylchloride (390 mg, 1.85 mmol) in portions. The reaction mixture wasstirred at rt for 18 h, then diluted with CH₂Cl₂, and washedsuccessively with 1 N HCl, 1 M aq NaHCO₃, and brine. The organic layerwas dried over Na₂SO₄ and filtered. Evaporation of the solvent affordeda solid that was then purified by sgc (3:1 hexanes-EtOAc) to give 690 mg(92%) of Compound 68.

[0400] Step 5. To a solution of Compound 68 (380 mg, 0.92 mmol) in THF(10 mL) at −78° C. was added n-BuLi (0.81 mL, 2.5 M in hexanes, 2.0mmol). The solution was stirred at −78° C. for 30 min.Bis(2-fluorophenyl) disulfide (467 mg, 1.84 mmol) in THF (5 mL) wasadded dropwise. The reaction mixture was allowed to warm slowly to rt,and was stirred for 18 h. The reaction mixture was diluted with EtOAcand washed with water and brine, dried over Na₂SO₄, and filtered.Evaporation of the solvent gave a crude solid that was then purified bysgc (3:1 hexanes-EtOAc) to give 400 mg (81%) of Compound 69.

[0401] Step 6. A mixture of Compound 69 (340 mg, 0.63 mmol) and MCPBA(550 mg, 3.187 mmol) in CH₂Cl₂ (30 mL) was stirred at rt for 18 h. Thereaction mixture was diluted with CH₂Cl₂, washed successively with 1 Maq. NaHCO₃ and brine, dried over Na₂SO₄, and filtered. Removal ofsolvent yielded a white solid that was purified by sgc (3:1hexanes-EtOAc) to give 218 mg (61%) of Compound 70.

[0402] Step 7. To a solution of Compound 70 (210 mg, 0.37 mmol) in1,4-dioxane (5 mL) was added a solution of lithium hydroxide hydrate(155 mg, 3.7 mmol) in water (1 mL). The reaction mixture was stirred atrt for 18 h, then extracted with EtOAc. The organic phase was washedsuccessively with water and brine, dried over Na₂SO₄, and filtered.Removal of solvent afforded 165 mg (94%) of Compound 71.

[0403] Step 8. Compound BF To a solution of Compound 71 (160 mg, 0.34mmol) and triethylamine (1 mL, 0.73 g, 7.1 mmol) in CH₂Cl₂ (10 mL) at−78° C. was added a solution of trifluoromethanesulfonic anhydride (0.06mL, 100 mg, 0.36 mmol) in CH₂Cl₂ (2 mL). The reaction mixture wasstirred at −78° C. for 15 min, then diluted with CH₂Cl₂, and washedsuccessively with 1 N HCl, 1 M aq. NaHCO₃, and brine. The organic layerwas dried over Na₂SO₄ and filtered. Evaporation of the solvent yielded asolid that was purified by sgc (3:1 hexane-EtOAc) to give 110 mg (53%)of Compound 72 (BF).

EXAMPLE XV

[0404]

[0405] Step 1. Compound 73 was prepared in essentially the same manneras described in Example XIV starting at Step 2 substituting4-(aminomethyl) piperidine for compound 65 and substitutingp-methoxybenzenesulfonyl chloride for p-chlorobenzenesulfonyl chloridein Step 4.

[0406] Step 2. To a solution of Compound 73 (837 mg, 1.55 mmol) inCH₂Cl₂ (10 mL) at −78° C. was added boron tribromide solution (4.6 mL,1.0 M in CH₂Cl₂, 4.6 mmol). The reaction mixture was stirred at −78° C.for 15 min, then at 0° C. for 2 h, and then at rt for 48 hr. Thereaction mixture was diluted with Et₂O and CH₂Cl₂, and saturated aq.NaHCO₃ was added. The aq. phase was extracted further with CH₂Cl₂. Thecombined organic layers were washed successively with saturated aq.NaHCO₃ and brine, dried over Na₂SO₄, and filtered. Removal of thesolvent afforded 300 mg of Compound 74.

[0407] Step 3. Compound CE A solution of Compound 74 (300 mg, 0.572mmol) and cesium carbonate (1 g, 3.1 mmol) in DMF (5 mL) was heated to90° C. and allowed to return to rt. Bromodifluoromethane gas was bubbledthrough the solution for 5 min. The reaction mixture was stirred at 90°C. for 3 h, then at rt for 15 h. The reaction mixture was diluted withEtOAc and washed successively with water and brine. The organic layerwas dried over Na₂SO₄ and filtered. Evaporation of the solvent, followedby purification of the crude product by sgc (30% EtOAc in hexanes) gave220 mg of Compound 75 (CE).

EXAMPLE XVI

[0408]

[0409] Step 1. A solution of Compound 4 (832 mg, 1.60 mmol) and TFA (1.2mL, 1.8 g, 16 mmol) in CH₂Cl₂ (10 mL) was stirred at rt for 15 h, andthen partitioned between EtOAc and 0.1 M aq. NaOH solution. The organiclayer was extracted further 0.1 M aq. NaOH solution. The combined aq.layers were adjusted to pH ˜1 with 1 N hydrochloric acid, then extractedwith EtOAc (5×50 mL). The combined organic extracts were washed withbrine, dried over MgSO₄, and filtered. Removal of the solvent, followedby storage under reduced (˜0.1 mm Hg) pressure gave 673 mg (91%) ofCompound 76.

[0410] Step 2. Pentafluorophenol (1.85 g, 10.1 mmol) and EDCl. HCl (1.93g, 10.1 mmol) were added successively to a solution of Compound 76 (2.34g, 5.03 mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred at rtfor 18 h, then diluted with CH₂Cl₂ and washed successively with water,saturated aq. NaHCO₃, and brine. The organic layer was dried over MgSO₄and filtered. Removal of solvent, followed by purification of theresulting crude residue by sgc (2:1 hexanes-EtOAc) gave 3.02 g (95%) ofCompound 77.

[0411] Step 3. Compound H To a suspension of sodium hydride (15 mg, 60%dispersion in mineral oil; 9.2 mg, 0.38 mmol) in DMF (275 μL) was added2-propanol (40 μL, 31 mg, 0.52 mmol). The resulting solution was stirredat rt for 5 min. Compound 77 (110 mg, 0.174 mmol) was then added in oneportion. The reaction mixture was stirred for 75 min, then diluted withEtOAc and poured into saturated aq. NaHSO₄ solution. The aq. layer wasextracted further with EtOAc. The combined extracts were washed withsaturated aq. NaHCO₃, water, and brine, then dried over MgSO₄, andfiltered. Removal of solvent, followed by purification of the resultingoil by sgc (2:1 hexanes-EtOAc) gave 55 mg (63%) of Compound 78 (H).

EXAMPLE XVII

[0412]

[0413] Step 1. A mixture of 4-(trifluoroacetamidomethyl)piperidiniumtrifluoroacetate (5.0 g, 11.4 mmol) and triethylamine (3.5 mL, 2.5 g, 25mmol) in CH₂Cl₂ (40 mL) was cooled to 0° C. and a solution of2-nitrobenzenesulfonyl chloride (2.53 g, 11.4 mmol) in CH₂Cl₂ (20 mL)was added. The ice bath was removed and the reaction was allowed toproceed at rt for 18 h. The reaction mixture was poured into water. Thelayers were separated and the aq. layer was extracted with CH₂Cl₂. Thecombined organic layers were washed with brine, dried over MgSO₄, andfiltered. The solvent was evaporated to afford 4.4 g (97%) of Compound79.

[0414] Step 2. To a solution of Compound 79 (2.7 g, 6.8 mmol) in MeOH(27 mL) was added a solution of lithium hydroxide (0.20 g, 8.4 mmol) inwater (6 mL). The reaction mixture was stirred at rt for 18 h, thendiluted with CH₂Cl₂ and washed with water. The organic layer was driedover Na₂SO₄ and filtered. Evaporation of the solvent afforded 1.95 g(95%) of Compound 80.

[0415] Step 3. A solution of Compound 80 (1.29 g, 4.31 mmol) andtriethylamine (0.66 mL, 0.48 g, 4.7 mmol) in CH₂Cl₂ (40 mL) was cooledto 0° C. and MsCl (0.74 mL, 0.54 g, 4.7 mmol) was added dropwise. Thesolution was allowed to warm to rt and was then stirred at rt for 18 h.The reaction mixture was diluted with CH₂Cl₂ and washed successivelywith water and brine. The organic phase was dried over Na₂SO₄ andfiltered. Removal of the solvent afforded a 1.59 g (98%) of Compound 81.

[0416] Step 4. A mixture of Compound 81 (1.59 g, 4.21 mmol), conc.hydrochloric acid (0.1 mL), and 10% palladium on carbon (0.1 g) in MeOH(30 mL) was shaken under hydrogen atmosphere (30 psi) for 1 h. Thecatalyst was removed by filtration. The filtrate was diluted with CH₂Cl₂and washed successively with saturated NaHCO₃ and water The organicextracts were dried over Na₂SO₄ and filtered. Evaporation of the solventafforded 1.42 g (97%) of Compound 82.

[0417] Step 5. Compound AJ A solution of Compound 82 (0.10 g, 0.29mmol), triethylamine (44 μL, 32 mg, 0.32 mmol), and cyclopentanecarbonylchloride (42 mg, 0.32 mmol) in CH₂Cl₂ was stirred at rt for 18 h. Thereaction mixture was diluted with CH₂Cl₂ and washed with 1 N HCl andwater. The organic phase was dried over Na₂SO₄ and filtered. Removal ofthe solvent afforded a crude solid that was purified by PTLC (5:1CH₂Cl₂-Et₂O) to give 72 mg (56%) of Compound 83 (AJ).

EXAMPLE XVIII

[0418]

[0419] Step 1. A mixture of 4-(methanesulfonamidomethyl)piperidiniumtrifluoroacetate (0.5 g, 1.6 mmol) and triethylamine (0.5 mL, 0.36 g,3.6 mmol) in CH₂Cl₂ (10 mL) was cooled to 0° C. and a solution of5-bromo-2-thiophenesulfonyl chloride (0.37 g, 1.6 mmol) in CH₂Cl₂ (5 mL)was added. The ice bath was removed and the reaction was allowed toproceed at rt for 18 h. The reaction mixture was poured into water. Thelayers were separated and the aq. layer was extracted with CH₂Cl₂. Thecombined organic layers were washed with water, dried over MgSO₄, andfiltered. The solvent was evaporated to afford 0.60 g (89%) of Compound84.

[0420] Step 2. Compound W

[0421] Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), wasadded to a solution of Compound 84 (0.21 g, 0.50 mmol) in THF (6 mL) andthe resulting solution was stirred under a nitrogen atmosphere, at rtfor 30 min. A solution of potassium carbonate (70 mg, 0.51 mmol) inwater (1 mL), followed by phenylboronic acid (74 mg, 0.61 mmol), wasadded. The reaction mixture was stirred at reflux, under a nitrogenatmosphere for 24 h, then allowed to cool to rt. The reaction wasdiluted with EtOAc and washed successively with water and brine, driedover Na₂SO₄, and filtered. Removal of the solvent yielded a crudeproduct that was purified by PTLC (3:1 CH₂Cl₂-Et₂O) to give 72 mg (35%)of Compound 85 (W).

EXAMPLE XIX

[0422]

[0423] Step 1. To a suspension of aluminum trichloride (19.1 g, 0.143mol) in CH₂Cl₂ (30 mL) at −78° C. was added, dropwise over 1 h, asolution of thiophene (12.0 g, 0.143 mol) and t-butyl bromide (19.6 g,0.143 mol) in CH₂Cl₂ (30 mL). The reaction mixture was stirred at −78°C. for 2 h, then allowed to warm to rt, and stirred for a further 18 h.The reaction mixture was diluted with CH₂Cl₂, and washed with water, 5%NaOH, and water. The organic layer was dried over Na₂SO₄ and filtered.Removal of the solvent under reduced pressure afforded a liquid that waspurified by vacuum distillation (˜20 mmHg) to give 10.7 g (53%) ofCompound 86.

[0424] Step 2. A solution of Compound 86 (1.40 g, 9.98 mmol) in CH₂Cl₂(10 mL) was added dropwise to an ice-cold solution of chlorosulfonicacid (3.5 g, 30 mmol) in CH₂Cl₂ (30 mL). The reaction mixture wasstirred for 30 min at 0° C., and then poured into ice. The aq. solutionwas extracted with CH₂Cl₂. The organic phase was washed with H₂O, driedover Na₂SO₄, and filtered. Evaporation of the solvent gave 2.11 g (89%)of Compound 87.

[0425] Step 3. A mixture of 4-(trifluoroacetamidomethyl)piperidiniumtrifluoroacetate (3.87 g, 8.8 mmol) and triethylamine (2.7 mL, 2.0 g,19.5 mmol) in CH₂Cl₂ (30 mL) was cooled to 0° C. and a solution ofCompound 87 (2.11 g, 8.84 mmol) in CH₂Cl₂ (5 mL) was added. The ice bathwas removed and the reaction was allowed to proceed at rt for 4 h. Thereaction mixture was poured into water. The layers were separated andthe aq. layer was extracted with EtOAc. The combined organic layers werewashed with water, dried over Na₂SO₄. and filtered. The solvent wasevaporated to afford a solid that was then purified by sgc (3:1hexanes-EtOAc) to give 3.30 g (90%) of Compound 88.

[0426] Step 4. To a solution of Compound 88 (1.82 g, 4.41 mmol) in1,4-dioxane (90 mL) was added aq. lithium hydroxide solution (90 mL, 1.0M). The reaction mixture was stirred at rt for 3 h, then diluted withCH₂Cl₂ and washed with water. The organic phase was dried over Na₂SO₄and filtered. Evaporation of the solvent gave 1.52 g (100%) of Compound89.

[0427] Step 5. Compound CU A solution of Compound 89 (0.17 g, 0.54 mmol)and triethylamine (0.087 mL, 0.063 g, 0.60 mmol) in CH₂Cl₂ (5 mL) wascooled to 0° C. and MsCl (0.046 mL, 68 mg, 0:59 mmol) was addeddropwise. The solution was allowed to warm to rt and was then stirred atrt for 3 h. The reaction mixture was diluted with CH₂Cl₂ and washed withwater. The organic phase was dried over Na₂SO₄ and filtered. Removal ofthe solvent afforded a residue that was then purified by sgc (2:1hexanes-EtOAc) to give 74 mg (35%) of Compound 90 (CU).

[0428] It will be understood that various modifications may be made tothe embodiments and examples disclosed herein. Therefore, the abovedescription should not be construed as limiting, but merely asexemplifications of preferred embodiments. Those skilled in the art willenvision various modifications within the scope and spirit of the claimsappended hereto.

We claim:
 1. A compound of the formula I:

or a pharmaceutically acceptable salt or solvate of said compound,wherein: L¹ is a covalent bond, —CH₂—, —C(O)—, —C(O)O—, —S(O₂)—, —S(O)—,—S—, —O—, —NH—, or —N(R⁷)—; L² is —CH₂—, —C(H)(alkyl)-, —C(alkyl)₂-,—C(O)—, —SO—, —S(O_(2,))—, —C(═NR⁷)—, —C(═N—CN)— or —C(═N—OR⁷); L³ is acovalent bond, —C(O)— or —S(O₂)—; R¹ is selected from the groupconsisting of H, halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,heterocyclylalkyl, —NHR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —S(O₂)R⁷,—Si(alkyl)_(n)(aryl)_(3−n), aryl and heteroaryl, wherein each of saidaryl or heteroaryl can be unsubstituted or optionally independentlysubstituted with one to five moieties which can be the same or differentand are independently selected from the group consisting of halogen,alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkoxy, alkoxy,—N(R⁷)₂, —C(O)OR⁷, —C(O)N(R⁷)₂, —NC(O)R⁷, —NC(O)OR⁷, —NC(O)N(R⁷)₂, —NO₂,—CN, —S(O₂)R⁷, —S(O₂)N(R⁷)₂, —NC(═N—CN)NHR⁷, and OH, with the provisothat: e) when R¹ is halogen, L¹ is a covalent bond; f) when R¹ is —NHR⁷or —N(R⁷)₂, L¹ is a covalent bond, —CH₂—, —C(O)—, —S(O₂)— or —SO—; g)when R¹ is —C(O)R⁷ or —C(O)OR⁷, L¹ is a covalent bond, —CH₂—, —NH— or—N(alkyl)-; and h) when R¹ is —S(O₂)R⁷ or —C(O)OR⁷, L¹ is a covalentbond, —CH₂—, —NH— or —N(alkyl)-; R² is H, —OH, halogen, —N(R⁷)₂—, —CF₃,alkoxy, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl; R³ and R⁴ arethe same or different, and are independently H or alkyl, or R³ and R⁴taken together form a carbonyl group, i.e. C(═O); R⁵ is H or alkyl; R⁶is selected from the group consisting of H, alkyl, haloalkyl,cycloalkyl, NHR⁷, N(R⁷)₂, aryl and heteroaryl, wherein each of said aryland heteroaryl can be unsubstituted or optionally independentlysubstituted with one to five moieties which moieties can be the same ordifferent and are independently selected from the group consisting ofhalogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy and OH; R⁷ isselected from H, alkyl, haloalkyl, cycloalkyl, heterocyclylalkyl, aryland heteroaryl, wherein each of said aryl and heteroaryl can beunsubstituted or optionally independently substituted with one to fivemoieties which moieties can be the same or different and areindependently selected from the group consisting of halogen, alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy and/or OH; A is selected fromphenyl, naphthyl, pyridyl, thienyl, thiazolyl, and indolyl, quinolyl,isoquinolyl, pyrazinyl, pyridazinyl, furanyl, pyrrolyl, pyrimidyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzofuranyl,benzothienyl; X is independently selected from the group consisting ofH, halogen, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy,alkoxycarbonyl, haloalkoxy, —N(R⁷)₂, —N(R⁷)(C(O)R⁷), —N(R⁷)(C(O)OR⁷),—NO₂ and —CN, and when A is selected from the group consisting ofpyridyl, thienyl, thiazolyl, indolyl, quinolyl, isoquinolyl, pyrazinyl,pyridazinyl, pyrrolyl, pyrimidyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, and benzothienyl, X can be oxide]; and n is0-3, with the proviso that (i) the two R⁷ moieties in —N(R⁷)₂ can be thesame or different and are independently selected, and (ii) the moiety—N(R⁵)—L³—R⁶ can optionally form a ring system.
 2. A compound accordingto claim 1 wherein L¹ is —CH₂—, —C(O)—, —S(O)—, —C(O)O—, or —S(O₂)—;L²is —CH₂—, —CH(alkyl), —C(alkyl)₂-, —C(O)—, —SO— or —S(O₂)—; L³is—C(O)— or —S(O₂)—; R¹ is alkyl, haloalkyl, cycloalkyl, aryl orheteroaryl, wherein said aryl and heteroaryl can be unsubstituted oroptionally independently substituted with one to five moieties which canbe the same or different and are independently selected from the groupconsisting of halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy,—N(R⁷)₂, —CN, (C₁-C₆)alkoxy and OH; R² is H, OH, halogen, CF₃, alkoxy,—N(R⁷)₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —CH₂—(C₃-C₅)cycloalkyl, or(C₃-C₅)cycloalkyl; R³ and R⁴ are the same or different, and areindependently selected from H or (C₁-C₆)alkyl; R⁵ is H or (C₁-C₆)alkyl;R⁶is H, (C₁-C₆)alkyl, or haloalkyl; A is phenyl, naphthyl, indolyl,furanyl or pyridyl; X is selected from the group consisting of H,halogen, alkyl, haloalkyl, (C₃-C₅)cycloalkyl, hydroxy, alkoxy, andhaloalkoxy and n is 0-2.
 3. A compound according to claim 1 wherein L¹is —CH₂—, —C(O)O— or —S(O₂)—; L²is —CH₂— or —S(O₂)—; L³is —C(O)— orS(O₂)—; R¹ is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, whereinsaid aryl and heteroaryl can be unsubstituted or optionallyindependently substituted with one to five moieties which can be thesame or different and are independently selected from the groupconsisting of halogen, alkyl, cycloalkyl, haloalkyl, haloalkoxy,(C₁-C₆)alkoxy and OH; R² is H, OH, halogen, CF₃, alkoxy, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, —CH₂—(C₃-C₅)cycloalkyl or (C₃-C₅)cycloalkyl; R³ and R⁴are H; R⁵ is H or C₁-C₆ alkyl; R⁶ is H, C₁-C₆ alkyl, or haloalkyl; A isphenyl, indolyl or pyridyl; X is selected from the group consisting ofH, halogen, alkyl, haloalkyl, (C₃-C₅)cycloalkyl, hydroxy, alkoxy, andhaloalkoxy and n is 0-2.
 4. The compound according to claim 1 having theformula 2:

wherein: L³ is —C(O)— or —S(O₂)—; R¹ is alkyl, haloalkyl, cycloalkyl,aryl or heteroaryl, wherein said aryl and heteroaryl can beunsubstituted or optionally independently substituted with one to fivemoieties which can be the same or different and are independentlyselected from the group consisting of halogen, alkyl, cycloalkyl,haloalkyl, haloalkoxy, (C₁-C₆)alkoxy and OH; R² is H, OH, F,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, alkoxy or (C₃-C₅)cycloalkyl; R⁶ is H,C₁-C₆ alkyl, or haloalkyl; X is selected from the group consisting of H,halogen, alkyl, haloalkyl, (C₃-C₅)cycloalkyl alkoxy, hydroxy andhaloalkoxy and n is 0-2.
 5. The compound according to claim 1 having theformula 3:

wherein: L³ is —C(O)— or —S(O₂)—; R¹ is alkyl, haloalkyl, cycloalkyl,aryl or heteroaryl, wherein said aryl and heteroaryl can beunsubstituted or optionally independently substituted with one to fivemoieties which can be the same or different and are independentlyselected from the group consisting of halogen, alkyl, cycloalkyl,haloalkyl, haloalkoxy, (C₁-C₆)alkoxy and OH; R² is H, OH, F,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, alkoxy or (C₃-C₅)cycloalkyl; R⁶ is H,C₁-C₆ alkyl, or haloalkyl; X is selected from the group consisting of H,halogen, alkyl, haloalkyl, (C₃-C₅)cycloalkyl, alkoxy, hydroxy andhaloalkoxy and n is 0-2.
 6. The compound according to claim 1 having theformula 4:

wherein: L³ is —C(O)— or —S(O₂); R¹ is alkyl, haloalkyl, cycloalkyl,aryl or heteroaryl, wherein said aryl and heteroaryl can beunsubstituted or optionally independently substituted with one to fivemoieties which can be the same or different and are independentlyselected from the group consisting of halogen, alkyl, cycloalkyl,haloalkyl, haloalkoxy, (C₁-C₆)alkoxy and OH; R² is H, OH, F,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, alkoxy or (C₃-C₅)cycloalkyl,CH₂—(C₃-C₅)cycloalkyl; R⁶ is H, C₁-C₆ alkyl, or haloalkyl; X is selectedfrom the group consisting of H, halogen, alkyl, haloalkyl,(C₃-C₅)cycloalkyl, alkoxy, hydroxy and haloalkoxy; and n is 0-2.
 7. Thecompound according to claim 1 having the formula 5:

wherein: L³ is —C(O)— or —S(O₂)—; R¹ is alkyl, haloalkyl, cycloalkyl,aryl or heteroaryl, wherein said aryl and heteroaryl can beunsubstituted or optionally independently substituted with one to fivemoieties which can be the same or different and are independentlyselected from the group consisting of halogen, alkyl, cycloalkyl,haloalkyl, haloalkoxy, (C₁-C₆)alkoxy and OH; R² is H, OH, F,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, alkoxy or (C₃-C₅)cycloalkyl,CH₂—(C₃-C₅)cycloalkyl; R⁶ is H, C₁-C₆ alkyl, or haloalkyl; R⁵ is H,alkyl or aryl; X is selected from H, halogen, alkyl, haloalkyl,(C₃-C₅)cycloalkyl, alkoxy, hydroxy and haloalkoxy; and n is 0-2.
 8. Thecompound according to claim 1 wherein: L¹ is —C(O)O— or —S(O₂)—; L² is—S(O₂)—; L³ is —C(O)— or —S(O₂)—; R¹ is selected from the groupconsisting of t-butyl, i-propyl, neopentyl, 2-trifluoromethyl-2-propyl,1,1-bis(trifluoromethyl)-1-ethyl, 2-fluorophenyl, 2,6-difluorophenyl,2-pyridyl, and 2-pyrimidyl; R² is H, F, (C₁-C₆)alkyl, OH, or alkoxy;R³═R⁴═H; R⁵ is H; R⁶ is CH₃ or CF₃; A is phenyl, indolyl or pyridyl; Xis selected from the group consisting of H, F, Cl, Br, CF₃, —OCH₃, —OCF₃and —OCHF₂; and n is 0-2.
 9. The compound according to claim 1 of theformula:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁶, A, L¹, L², L³ and X are as set forth in the following table: Cmp R¹R² R³ R⁴ R⁶ A = L¹ L² L³ X A

H H H CF₃

CO₂ SO₂ SO₂ Cl B

H H H CH₃

CO₂ SO₂ SO₂ OCF₃ C

H H H CF₃

CO₂ SO₂ SO₂ Cl D

H H H CF₃

CO₂ SO₂ SO₂ H E

H H H CF₃

CO₂ SO₂ SO₂ Cl F

H H H CH₃

CO₂ SO₂ SO₂ Cl G

H H H CF₃

CO₂ SO₂ SO₂ Cl H i-propyl H H H CF₃

CO₂ SO₂ SO₂ Cl I

H H H CH₃

CO₂ SO₂ SO₂ H J

H H H CH₃

SO₂ SO₂ SO₂ OCH₃ K

H H H CH₃

SO₂ SO₂ SO₂ OCH₃ L

H H H CH₃

SO₂ SO₂ SO₂ OCF₂H M

H H H CH₃

SO₂ SO₂ SO₂ OCF₃ N

H H H C₂H₅

SO₂ SO₂ SO₂ OCF₂H O

H H H CH₃

SO₂ SO₂ SO₂ Cl P

H H H C₂H₅

SO₂ SO₂ SO₂ OCF₃ Q

H H H CF₃

SO₂ SO₂ SO₂ CF₃ R

H H H CF₃

SO₂ SO₂ SO₂ Cl S

H H H CF₃

SO₂ SO₂ C═O OCH₃ T

H H H CH₃

SO₂ SO₂ SO₂ H U

H H H CF₃

SO₂ SO₂ C═O OCH₃ V Br H H H CH₃

CB SO₂ SO₂ H W

H H H CH₃

CB SO₂ SO₂ H X C₃H₇ H H H CH₃

SO₂ SO₂ SO₂ OCH₃ Y

H H H CF₃

SO SO₂ C═O Cl Z

H H H CF₃

SO₂ CH₂ C═O Cl AA

H H H CF₃

S CH₂ C═O Cl AB

H H H CH₃

CH₂ SO₂ SO₂ Cl AC

H H H CH₃

CH₂ SO₂ SO₂ Cl AD

H H H CH₃

C═O SO₂ SO₂ Cl AE H H H H CF₃

CB SO₂ SO₂ H AF H H H H CH₃

CB SO₂ SO₂ H AG

H H H CH₃

SO₂ SO₂ SO₂ H AH Si(CH₃)₃ H H H CH₃

CB SO₂ SO₂ Cl AI Br H H H CH₃

CB SO₂ SO₂ H AJ

H H H CH₃

NH SO₂ SO₂ H AK

OCH₃ H H CH₃

CO₂ SO₂ SO₂ Cl AL

CH₃ H H CF₃

SO₂ SO₂ SO₂ Cl AM

CH₃ H H CH₃

SO₂ SO₂ SO₂ Cl AN

CH₃ H H CF₃

CO₂ SO₂ SO₂ Cl AO

H H H CF₃

SO₂ SO₂ SO₂ H AP

H H H CF₃

CO₂ SO₂ SO₂ OCH₃ AQ

F H H CF₃

SO₂ SO₂ SO₂ Cl AR

F H H CF₃

CO₂ SO₂ SO₂ Cl AS

F H H CF₃

SO₂ SO₂ SO₂ Cl AT

F H H CF₃

SO₂ SO₂ SO₂ H AU

F H H CF₃

SO₂ SO₂ SO₂ Cl AV

OCH₃ H H CF₃

SO₂ SO₂ SO₂ Cl AW

OCH₃ H H CF₃

SO SO₂ SO₂ Cl AX

OCH₃ H H CF₃

CO₂ SO₂ SO₂ Cl AY

H H H CH₃

SO₂ SO₂ SO₂ OCF₃ AZ

H H H CF₃

SO₂ SO₂ SO₂ OCF₃ BA

H H H CF₃

SO₂ SO₂ SO₂ Cl BB

H H H CF₃

SO₂ SO₂ SO₂ H BC

H H H CH₃

SO₂ SO₂ SO₂ H BD

H H H CF₃

CO₂ SO₂ SO₂ OCF₃ BE

H H H CF₃

CO₂ SO₂ SO₂ Cl BF

H CH₃ CH₃ CF₃

SO₂ SO₂ SO₂ Cl BG

H CH₃ CH₃ CF₃

SO₂ SO₂ C═O CF₃ BH

H CH₃ CH₃ CF₃

SO₂ SO₂ C═O Cl BI

H CH₃ CH₃ CF₃

SO₂ SO₂ SO₂ CF₃ BJ

H CH₃ CH₃ H

SO₂ SO₂ CB CF₃ BK

H CH₃ CH₃ CF₃

CO₂ SO₂ SO₂ Cl BL

F H H CF₃

SO₂ SO₂ SO₂ CF₃ BM

OCH₃ H H CF₃

S SO₂ SO₂ Cl BN

F H H CF₃

CO₂ SO₂ SO₂ CF₃ BO

F H H CF₃

SO₂ SO₂ SO₂ Cl BP

OH H H CF₃

CO₂ SO₂ SO₂ Cl BQ

H H CH₃

CO₂ SO₂ SO₂ Cl BR

F H H CF₃

SO₂ SO₂ SO₂ Cl BS

H H CH₃

CO₂ SO₂ SO₂ Cl BT

CH₃ H H CF₃

SO₂ SO₂ C═O Cl BU

H H CF₃

CO₂ SO₂ SO₂ Cl BV

OH H H CH₃

CO₂ SO₂ SO₂ Cl BW

F H H CF₃

SO₂ SO₂ C═O Cl BX

C₃H₇ H H CF₃

CO₂ SO₂ SO₂ Cl BY

F H H CF₃

SO₂ SO₂ SO₂ Cl BZ

H H CF₃

CO₂ SO₂ SO₂ Cl CA

H H H CF₃

SO₂ SO₂ C═O Cl CB

H H H CF₃

SO₂ SO₂ SO₂ H CC

H H H CF₃

SO₂ SO₂ SO₂ Cl CD

H H H CF₃

SO₂ SO₂ C═O Cl CE

H H H CF₃

SO₂ SO₂ C═O OCF₂H CF

H H H CH₃

SO₂ SO₂ SO₂ H CG

H H H CF₃

SO₂ SO₂ C═O H CH

H H H CF₃

SO₂ SO₂ C═O OCH₃ CI

H H H C₂H₅

SO₂ SO₂ SO₂ OCF₃ CJ

H H H CH₃

SO₂ SO₂ SO₂ OCF₃ CK

H H H CF₃

SO₂ SO₂ SO₂ OCF₃ CL

H H H CF₃

SO₂ SO₂ C═O OCF₃ CM

H H H CF₃

SO₂ SO₂ C═O CF₃ CN

H H H CF₃

SO₂ SO₂ C═O OCF₃ CO

H H H CH₃

SO₂ SO₂ SO₂ Cl CP C₄H₉ H H H CH₃

SO₂ SO₂ SO₂ Cl CQ

H H H C₂H₅

CO₂ SO₂ SO₂ Cl CR CH₃ H H H CF₃

CO₂ SO₂ C═O H CS

H H H CF₃

CO₂ SO₂ SO₂ CF₃ CT

H H H CF₃

CB SO₂ C═O H CU

H H H CH₃

CB SO₂ SO₂ H CV Cl H H H CH₃

CB SO₂ SO₂ Br CW

H H H CH₃

CB SO₂ SO₂ H CX

F H H CF₃

CO₂ SO₂ C═O Cl CY H H H H CH₃

CB SO₂ SO₂ H CZ

H H H CF₃

SO₂ C═O SO₂ H DA

F H H CF₃

SO SO₂ SO₂ Cl DB

F H H CF₃

SO SO₂ SO₂ Cl DC

H H H CF₃

SO₂ CH₂ C═O OCF₃ DD CH₃ H O* O* H

CO₂ SO₂ CB H DE

H H H CH₃

CB SO₂ SO₂ H DF

H H H CH₃

CB SO₂ SO₂ H DG

H H H N(CH₃)₂

CO₂ SO₂ SO₂ Cl DH Br H H H CH₃

CB SO₂ SO₂ H DI CH₃ H H H CH₃

CB SO₂ SO₂ t-butyl DJ

F H H CF₃

CO₂ SO₂ SO₂ H DK

OCH₃ H H CF₃

SO₂ SO₂ SO₂ Cl DL

OC₂H₅ H H H

S SO₂ CB Cl DM

OCH₃ H H CH₃

SO₂ SO₂ SO₂ Cl DN

F H H CF₃

SO SO₂ SO₂ Cl DO

OC₂H₅ H H CF₃

SO₂ SO₂ SO₂ Cl DP

OCH₃ H H CH₃

SO₂ SO₂ SO₂ Cl DQ

F H H CF₃

SO₂ SO₂ SO₂ Cl DR

F H H CF₃

SO₂ SO₂ SO₂ Cl DS

F H H CF₃

SO₂ SO₂ SO₂ Cl DT CH₃ H H H CH₃

SO₂ SO₂ SO₂ Cl DU

H H H CF₃

SO₂ CH₂ SO₂ H


10. The compound according to claim 1 having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁶, A,L¹, and X are as set forth in the following table: Cmp. R¹ R² R⁶ A L¹ XA

H CF₃

CO₂ Cl C

H CF₃

CO₂ Cl D

H CF₃

CO₂ H E

H CF₃

CO₂ Cl F

H CH₃

CO₂ Cl G

H CF₃

CO₂ Cl H i-propyl H CF₃

CO₂ Cl J

H CH₃

SO₂ OCH₃ L

H CH₃

SO₂ OCF₂H M

H CH₃

SO₂ OCF₃ N

H C₂H₅

SO₂ OCF₂H Q

H CF₃

SO₂ CF₃ AK

OCH₃ CH₃

CO₂ Cl AL

CH₃ CF₃

SO₂ Cl AM

CH₃ CH₃

SO₂ Cl AN

CH₃ CF₃

CO₂ Cl AO

H CF₃

SO₂ H AP

H CF₃

CO₂ OCH₃ AQ

F CF₃

SO₂ Cl AR

F CF₃

CO₂ Cl AS

F CF₃

SO₂ Cl AT

F CF₃

SO₂ H AU

F CF₃

SO₂ Cl AV

OCH₃ CF₃

SO₂ Cl AW

OCH₃ CF₃

SO Cl AX

OCH₃ CF₃

CO₂ Cl AZ

H CF₃

SO₂ OCF₃ BB

H CF₃

SO₂ H BD

H CF₃

CO₂ OCF₃ BE

H CF₃

CO₂ Cl DK

OCH₃ CF₃

SO₂ Cl DM

OCH₃ CH₃

SO₂ Cl DO

OC₂H₅ CF₃

SO₂ Cl DP

OCH₃ CH₃

SO₂ Cl EF

H CH₃

SO₂ OCH3 EG

H CH₃

SO₂ OH EH

F CF₃

SO₂ OCH3 EI

CH₃ CF₃

SO₂ H FG

H CF₃

SO₂ H FH

CH₃ CF₃

SO₂ H


11. The compound according to claim 1 having the formula:


12. The compound according to claim 1 having the formula:


13. The compound according to claim 1 having the formula:


14. The compound according to claim 1 having the formula:


15. The compound according to claim 1 having the formula:


16. The compound according to claim 1 having the formula:


17. The compound according to claim 1 having the formula:


18. The compound according to claim 1 having the formula:


19. The compound according to claim 1 having the formula:


20. The compound according to claim 1 having the formula:


21. The compound according to claim 1 having the formula:


22. The compound according to claim 1 having the formula:


23. The compound according to claim 1 having the formula:


24. The compound according to claim 1 having the formula:


25. The compound according to claim 1 having the formula:


26. The compound according to claim 1 having the formula:

wherein X and R² are the same as in claim 1; and R¹ is aryl orheteroaryl, wherein each of said aryl or heteroaryl can be unsubstitutedor optionally independently substituted with one to five moieties whichmoieties can be the same or different and are independently selectedfrom the group consisting of halogen, alky-cycloalkyl, haloalkyl,haloalkoxy, (C₁-C₆)alkoxy and OH;
 27. The compound according to claim 1having the formula:

wherein X is F, Cl, OH or CN; R¹ is aryl or heteroaryl, wherein each ofsaid aryl or heteroaryl can be unsubstituted or optionally independentlysubstituted with one to five X moieties; and R² is H, OH, F, CH₃, CF₃ orcyclopropyl.
 28. The compound according to claim 1 having the formula:

wherein X and R² are the same as in claim
 1. 29. The compound accordingto claim 1 having the formula:

wherein X is F, Cl, OH or CN; R¹ is aryl or heteroaryl, wherein each ofsaid aryl or heteroaryl can be unsubstituted or optionally independentlysubstituted with one to five X moieties; and R² is H, OH, F, CH₃, CF₃ orcyclopropyl. R⁵is H or alkyl
 30. The compound according to claim 29having the formula:


31. A pharmaceutical composition comprising an effective amount of acompound according to claim 1 and a pharmaceutically acceptable carrier.32. A pharmaceutical composition comprising an effective amount of acompound according to claim 9 and a pharmaceutically acceptable carrier.33. A pharmaceutical composition comprising an effective amount of acompound according to claim 10 and a pharmaceutically acceptablecarrier.
 34. A method of treating cancer, inflammatory diseases,immunomodulatory diseases, or respiratory diseases comprisingadministering to a mammal in need of such treatment an effective amountof a compound according to claim
 1. 35. A method of treating cutaneous Tcell lymphoma, rheumatoid arthritis, systemic lupus erythematosus,multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis,idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinaldisease, scleroderma, osteoporosis, renal ischemia, myocardialinfarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis,glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis,transplant rejection, atopic dermatitis, vasculitis, allergy, seasonalallergic rhinitis, Crohn's disease, inflammatory bowel disease,reversible airway obstruction, adult respiratory distress syndrome,asthma, chronic obstructive pulmonary disease (COPD) or bronchitiscomprising administering to a mammal in need of such treatment aneffective amount of a compound according to claim
 1. 36. The method ofclaim 35 wherein the condition or disease treated is selected from thegroup consisting of rheumatoid arthritis, multiple sclerosis, seasonalallergic rhinitis, psoriasis, transplant rejection and chronicobstructive pulmonary disease.
 37. A process for making a pharmaceuticalcomposition comprising combining a compound of claim 1 and apharmaceutically acceptable carrier.
 38. A method of treating rheumatoidarthritis comprising administering to a mammal in need thereof aneffective amount of a compound of claim 1 in combination with at leastone compound selected from the group consisting of a COX-2 inhibitor, aCOX-1 inhibitor, an immunosuppressive, a steroid and an anti-TNF-αcompound.
 39. A method of treating rheumatoid arthritis comprisingadministering to a mammal in need thereof an effective amount of acompound of claim 10 in combination with at least one compound selectedfrom the group consisting of a COX-2 inhibitor, a COX-1 inhibitor, animmunosuppressive, a steroid and an anti-TNF-α compound.
 40. The methodof claim 38 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1inhibitor is Feldene, the immunosuppressive is methotrexate,leflunomide, sulfasalazine, or cyclosporin, the steroid is β-methasoneand the anti-TNF-α compound is Enbrel or Remicade.
 41. The method ofclaim 39 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1inhibitor is Feldene, the immunosuppressive is methotrexate,leflunomide, sulfasalazine, or cyclosporin, the steroid is β-methasoneand the anti-TNF-α compound is Enbrel or Remicade.
 42. A composition fortreating rheumatoid arthritis which comprises an effective amount of acompound of claim 1 and a compound selected from the class consisting ofa COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroidand an anti-TNF-α compound.
 43. A composition for treating rheumatoidarthritis which comprises an effective amount of a compound of claim 10and a compound selected from the class consisting of a COX-2 inhibitor,a COX-1 inhibitor, an immunosuppressive, a steroid and an anti-TNF-αcompound.
 44. The composition of claim 42 wherein the COX-2 inhibitor isCelebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressiveis methotrexate, leflunomide, sulfasalazine, or cyclosporin, the steroidis β-methasone and the anti-TNF-α compound is Enbrel or Remicade. 45.The composition of claim 43 wherein the COX-2 inhibitor is Celebrex orVioxx, the COX-1 inhibitor is Feldene, the immunosuppressive ismethotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid isβ-methasone and the anti-TNF-α compound is Enbrel or Remicade.
 46. Amethod of treating multiple sclerosis comprising administering to amammal in need thereof an effective amount of a compound of claim 1 incombination with an effective amount of a compound selected from thegroup consisting of Avonex, Betaseron and Copaxone.
 47. A method oftreating multiple sclerosis comprising administering to a mammal in needthereof an effective amount of a compound of claim 10 in combinationwith an effective amount of a compound selected from the groupconsisting of Avonex, Betaseron and Copaxone.
 48. A composition fortreating multiple sclerosis which comprises an effective amount of acompound of claim 1 and a compound selected from Avonex, Betaseron andCopaxone.
 49. A composition for treating multiple sclerosis whichcomprises an effective amount of a compound of claim 10 and a compoundselected from the group consisting of Avonex, Betaseron and Copaxone.50. A method of treating psoriasis comprising administering to a mammalin need thereof an effective amount of a compound as defined in claim 1in combination with a compound selected from the group consisting of animmunosuppressive, a steroid and anti-TNF-α compound.
 51. A method oftreating psoriasis comprising administering to a mammal in need thereofan effective amount of a compound as defined in claim 10 in combinationwith a compound selected from the group consisting of animmunosuppressive, a steroid and anti-TNF-α compound.
 52. The method ofclaim 50 wherein the immunosuppressive is methotrexate, leflunomide,sulfasalazine or cyclosporin, the steroid is β-methasone and theanti-TNF-α compound is Enbrel or Remicade.
 53. The method of claim 51wherein the immunosuppressive is methotrexate, leflunomide,sulfasalazine or cyclosporin, the steroid is β-methasone and theanti-TNF-α compound is Enbrel or Remicade.
 54. A composition fortreating psoriasis which comprises an effective amount of a compound ofclaim 1 and a compound selected from the group consisting of animmunosuppressive, a steroid and anti-TNF-α compound.
 55. A compositionfor treating psoriasis which comprises an effective amount of a compoundof claim 10 and a compound selected from the group consisting of animmunosuppressive, a steroid and anti-TNF-α compound.
 56. Thecomposition of claim 54 wherein the immunosuppressive is methotrexate,leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasoneand the anti-TNF-α compound is Enbrel or Remicade.
 57. The compositionof claim 55 wherein the immunosuppressive is methotrexate, leflunomide,sulfasalazine or cyclosporin, the steroid is β-methasone and theanti-TNF-α compound is Enbrel or Remicade.
 58. A method of treatingseasonal allergic rhinitis and/or asthma comprising an effective amountof a compound of claim 1 in combination with an H1 antagonist.
 59. Acomposition for treating seasonal allergic rhinitis and/or asthma whichcomprises an effective amount of an H1 antagonist and an effectiveamount of a compound of claim
 1. 60. The composition of claim 59 whereinthe H1 antagonist is selected from the group consisting of Claritin,Clarinex, Zyrtec and Allegra.